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Breast Cancer Extratumor Microenvironment has Effect on Progression

Posted in Biochemical pathways, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Informatics, Cell Biology, Signaling & Cell Circuits, Clinical & Translational, Clinical Diagnostics, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diagnostics and Lab Tests, Disease Biology, Gene Regulation, Genome Biology, Genomic Endocrinology, Human Immune System in Health and in Disease, Lipid metabolism, Metabolism, Metabolomics, Micronutrients, Mutagenesis, tagged breast cancer, extratunot microenvironment, metastasis on February 20, 2016| Leave a Comment »

Breast Cancer Extratumor Microenvironment has Effect on Progression

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Tumor Microenvironment Diversity Predicts Breast Cancer Outcomes

GEN News Highlights   Feb 17, 2016   http://www.genengnews.com/gen-news-highlights/tumor-microenvironment-diversity-predicts-breast-cancer-outcomes/81252378/

 

Intratumor heterogeneity, it is known, can complicate cancer treatments. Now it appears the same may be true of tumor microenvironment heterogeneity. According to a new study from the Institute of Cancer Research (ICR), London, breast cancers that develop within an “ecologically diverse” breast cancer microenvironment are particularly likely to progress and lead to death.

The study took an unusual approach: It combined ecological scoring methods with genome-wide profiling data. This approach, besides showing clinical utility in the evaluation of breast cancer outcomes, demonstrated that even so contextual a discipline as genomics can benefit from being placed within a larger context. In this case, the context is essentially Darwinian, albeit at a small scale.

Natural selection is typically studied at the level of ecosystems consisting of animals and plants. In the current study, however, it was assessed at the level of the tumor microenvironment, which consists of cancer cells, immune system lymphocytes, and stromal cells.

The ICR scientists, led by Yinyin Yuan, Ph.D., presented their work February 16 in the journal PLoS Medicine, in an article entitled “Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis.” The article describes how the scientists developed a tumor ecosystem diversity index (EDI), a scoring system that indicates the degree of microenvironmental heterogeneity along three spatial dimensions in solid tumors. EDI scores take account of “fully automated histology image analysis coupled with statistical measures commonly used in ecology.”

“[EDI] was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set,” wrote the authors. “In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types.”

By using the EDI, the ICR team was able to identify several particularly aggressive subgroups of breast cancer. In fact, the EDI was a stronger predictor of survival than many established markers for the disease.

The ICR researchers also looked at the EDI in addition to genetic factors. For example, the researchers found that the prognostic value of EDI was enhanced with the addition of TP53 mutation status. By integrating EDI data and genome-wide profiling data, the researchers identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors. These tumors, which showed high microenvironmental diversity, substratified patients into poor prognostic groups.

“Our findings show that mathematical models of ecological diversity can spot more aggressive cancers,” said Dr. Yuan. “By analyzing images of the environment around a tumor based on Darwinian natural selection principles, we can predict survival in some breast cancer types even more effectively than many of the measures used now in the clinic.

“In the future, we hope that by combining cell diversity scores with other factors that influence cancer survival, such as genetics and tumor size, we will be able to tell apart patients with more or less aggressive disease so we can identify those who might need different types of treatment.”

“This ingenious study…teaches us a valuable lesson,” added Paul Workman, Ph.D., chief executive of the ICR. “[We] should always remember that cancer cells are not developing and growing in isolation, but are part of a complex ecosystem that involves normal human cells, too. By better understanding these ecosystems, we aim to create new ways to diagnose, monitor and treat cancer.”

 

Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

Rachael Natrajan, Heba Sailem, Faraz K. Mardakheh, Mar Arias Garcia, Christopher J. Tape, Mitch Dowsett, Chris Bakal, Yinyin Yuan    

 

    Feb 16, 2016   http://dx.doi.org:/10.1371/journal.pmed.1001961

 

Background

The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters.

Methods and Findings

We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10⁻⁴, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size.

Conclusions

To our knowledge, this is the first study to couple unbiased measures of microenvironmental heterogeneity with genomic alterations to predict breast cancer clinical outcome. We propose a clinically relevant role of microenvironmental heterogeneity for advanced breast tumors, and highlight that ecological statistics can be translated into medical advances for identifying a new type of biomarker and, furthermore, for understanding the synergistic interplay of microenvironmental heterogeneity with genomic alterations in cancer cells.

Background

The human body contains millions of cells, all of which grow, divide, and die in an orderly fashion to build tissues during early life and to replace worn-out or dying cells and repair injuries during adult life. Sometimes, however, normal cells acquire genetic changes (mutations) that allow them to divide uncontrollably and to move around the body (metastasize), resulting in cancer. Because any cell in the body can acquire the mutations needed for cancer development, there are many types of cancer. For example, breast cancer, the most common cancer in women, begins when the cells in the breast that normally make milk become altered. Moreover, different types of cancer progress and evolve differently—some cancers grow quickly and kill their “host” soon after diagnosis, whereas others can be successfully treated with drugs, surgery, or radiotherapy. The behavior of individual cancers depends both on the characteristics of the cancer cells within the tumor and on the interactions between the cancer cells and the normal stromal cells (the connective tissue cells of organs) and other cells (for example, immune cells) that surround and feed cancer cells (the tumor microenvironment).

Why Was This Study Done?

Although recent studies have highlighted the importance of the tumor microenvironment for disease-related outcomes, little is known about how the heterogeneity of the tumor microenvironment—the diversity of non-cancer cells within the tumor—affects outcomes. Mathematical modeling suggests that tumors with heterogeneous and homogeneous microenvironments have different growth patterns and that heterogeneous microenvironments are more likely to be associated with aggressive cancers than homogenous microenvironments. However, the lack of methods to quantify the spatial variability and cellular composition across solid tumors has prevented confirmation of these predictions. Here, the researchers develop a computational system for quantifying microenvironmental heterogeneity in breast cancer based on tumor morphology (shape and form) in histological sections (tissue samples taken from tumors that are examined microscopically). They then use this system to analyze the associations between clinical outcomes, molecular changes, and microenvironmental heterogeneity in breast cancer.

What Did the Researchers Do and Find?

The researchers used automated image analysis and statistical analysis to develop the ecosystem diversity index (EDI), a numerical measure of microenvironmental heterogeneity in solid tumors. They compared the EDI with prognosis (likely outcome), key mutations, genome-wide copy number (tumor cells often contain abnormal numbers of copies of specific genes), and expression profiling data (the expression of several key proteins is altered in tumors) in a test set of 510 samples from patients with breast cancer and in a validation set of 516 additional samples. Among high-grade breast cancers (grade 3 cancers; the grade of a cancer indicates what the cells look like; high-grade breast cancers have a poor prognosis), but not among low-grade breast cancers (grades 1 and 2), a high EDI (high microenvironmental heterogeneity) was associated with a poor prognosis. Specifically, patients with grade 3 tumors and a high EDI had a ten-year disease-specific survival rate of 51%, whereas the remaining patients with grade 3 tumors had a ten-year survival rate of 70%. Notably, the combination of a high EDI with specific DNA alterations—mutations in a gene called TP53 and loss of genes on Chromosomes 4p14 and 5q13—improved the accuracy of prognosis among patients with grade 3 breast cancer and stratified them into subgroups with disease-specific five-year survival rates of 35%, 9%, and 32%, respectively.

What Do These Findings Mean?

These findings establish a method for measuring the spatial heterogeneity of the microenvironment of solid tumors and suggest that the measurement of tumor microenvironmental heterogeneity can be coupled with information about genomic alterations to provide an accurate way to predict outcomes among patients with high-grade breast cancer. The association between EDI, specific genomic alterations, and outcomes needs to be confirmed in additional patients. However, these findings suggest that microenvironmental heterogeneity might provide an additional biomarker to help clinicians identify those patients with advanced breast cancer who have a particularly bad prognosis. The ability to identify these patients is important because it will help clinicians target aggressive treatments to individuals with a poor prognosis and avoid the overtreatment of patients whose prognosis is more favorable. Finally, and more generally, these findings describe a new way to investigate the interactions between the tumor microenvironment and genomic alterations in cancer cells.

Additional Information

This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001961.

• The US National Cancer Institute provides comprehensive information about cancer and its development (in English and Spanish), including detailed information about breast cancer and an online booklet for patients
• Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information about breast cancer and a science blog on the tumor microenvironment
• Breast Cancer Now is a not-for-profit organization that provides up-to-date information about breast cancer (in English and Spanish)
• The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
• Wikipedia has a page about the tumor microenvironment (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Citation: Natrajan R, Sailem H, Mardakheh FK, Arias Garcia M, Tape CJ, Dowsett M, et al. (2016) Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis.
PLoS Med 13(2): e1001961.     http://dx.doi.org:/10.1371/journal.pmed.1001961

http://journals.plos.org/plosmedicine/article/figure/image?size=large&id=info:doi/10.1371/journal.pmed.1001961.g001

Fig 1. In silico tumor dissection pipeline for quantifying spatial diversity in the tumor ecosystem. (A) Flow diagram depicting the overall study design. (B) Schematic of our pipeline for quantifying spatial diversity in pathological samples. H&E sections are morphologically classified and divided into regions to be spatially scored. The number of clusters k in the regional scores is indicative of the number of sub-populations of cell types in the tumor regions. (C) Examples of tumor regions with low and high diversity scores using the Shannon diversity index, accounting for cancer cells (outlined in green), lymphocytes (blue), and stromal cells (red). Cell classification is automated by image analysis. (D) The 3-D landscape of cell diversity scores on an example H&E section; the x- and y-axes are the geometric axes of the image, and the z-axis is cell diversity computed on a region-by-region basis. (E) The distribution of regional scores in a tumor from the METABRIC study with two regional clusters identified using Gaussian mixture clustering (grey shading: histogram; dashed black line: density; solid black lines: mixture components/clusters).

http://journals.plos.org/plosmedicine/article/figure/image?size=medium&id=info:doi/10.1371/journal.pmed.1001961.g002

Fig 2. Application of EDI to 1,026 breast tumors from the METABRIC study. (A) The frequencies of EDI scores in breast tumors. (B) H&E staining, distribution of classified cells (green: cancer; blue: lymphocyte; red: stromal cells), and the heatmap of regional diversity scores for a tumor with the highest EDI score (EDI = 5). (C) Representative regions from each of the clusters k1–k5 are shown in a tumor with EDI = 5, with cluster k1 having the lowest diversity score and k5 the highest. By mapping regional clusters to the H&E image, we can begin to interpret these clusters with different cell diversity. We observed predominantly cancer cells in k1, increasingly more stromal cells and ductal in situ carcinoma cells (DCIS) in k2, and a vessel in k3. Cluster k4 features extensive stromal lymphocytes between ductal in situ carcinoma components, while k5 shows tumor-infiltrating lymphocytes (TIL) associated with invasive carcinoma cells.

Fig 3. Reproducibility, stability, and independence of the EDI-high group in 507 grade 3 breast tumors.

http://journals.plos.org/plosmedicine/article/figure/image?size=large&id=info:doi/10.1371/journal.pmed.1001961.g003

Fig 3. Reproducibility, stability, and independence of the EDI-high group in 507 grade 3 breast tumors. (A) Kaplan–Meier curves of disease-specific survival to illustrate the prognosis of EDI-high samples compared to other grade 3 samples in two independent patient cohorts. Shown below the graph are the number of patients (the number of disease-specific events) per group for EDI-low (grey) and EDI-high (red). (B) Agreement of the EDI subtyping between 100% data and resampling with progressively fewer tumor regions in 200 repeats. (C) Distribution of known subtypes in grade 3 tumors stratified by EDI; asterisks mark subtypes enriched in the EDI-high group. (D) Kaplan–Meier curves illustrating the duration of disease-specific survival according to tumor size (left) and improvement of stratification with the addition of EDI information (right).

Accumulating evidence suggests that the interactions of cancer cells and stromal cells within their microenvironment govern disease progression, metastasis, and, ultimately, the evolution of therapeutic resistance [1–3]. Recent reports have highlighted the significance of the contribution of stromal gene expression and morphological structure as powerful prognostic determinants for a number of tumor types, emphasizing the importance of the tumor microenvironment in disease-related outcomes [4–7]. In breast cancer, a number of studies have demonstrated the prognostic correlation of individual cell types, including the immune cell infiltrate that predicts response to therapy [8–10], and the high percentage of tumor stroma that predicts poor prognosis in triple-negative disease but good prognosis in estrogen receptor (ER)–positive disease [11,12]. Nevertheless, different types of cells coexist with varying degrees of heterogeneity within a tumor. This fundamental feature of human tumors and the combinatorial effects of cell types have been largely ignored, and the collective implications for clinical outcome remain elusive. Consistent observations from mathematical models have highlighted that tumors with diverse microenvironments show growth patterns dramatically different from those of tumors with homogeneous environments [13] and are more likely to be associated with aggressive cancer phenotypes [2] that select for cell migration and eventual metastasis by allowing cancer cells to evolve more rapidly [14]. These observations highlight the need to understand the collective physiological characteristics and heterogeneity of tumor microenvironments. However, there is a lack of methods to quantify the high spatial variability and diverse cellular composition across different solid tumors. Moreover, the interplay of genomic alterations in cancer cells and microenvironmental heterogeneity and its subsequent role in treatment response have not been explored. Our aims were (i) to develop a computational system for quantifying microenvironmental heterogeneity based on tumor morphology in routine histological sections, (ii) to define the clinical implications of microenvironmental heterogeneity, and (iii) to integrate this histologybased index with RNA gene expression and DNA copy number profiling data to identify molecular changes associated with microenvironmental heterogeneity.

The Ecosystem Diversity Index To characterize the tumor ecosystem based on cell compositions, we developed a new index to be used in conjunction with our image analysis tool [16]. First, we used our automated morphological classification method [16] to identify and classify cells into cancer, lymphocyte, or stromal cell classes in H&E sections (Fig 1B). We next divided sections into smaller spatial regions and quantified the diversity of the tumor ecosystem in a tumor region j using the Shannon diversity index: dj ¼ Sm i pi logpi ; ð1Þ where m is the number of cell types and pi is the proportion of the ith cell type (Fig 1B and 1C). A high value of the Shannon diversity index dj reports a heterogeneous environment populated by many cell types, whilst a low value indicates a homogeneous environment (Fig 1C). Compared to other methods such as the Simpson index, the Shannon diversity index accounts for rare species and, hence, is less dominated by main species [17]. Subsequently, we derived the ecosystem diversity index (EDI) by applying unsupervised clustering that identifies the optimum number of clusters in the dataset in an unbiased manner, in order to group tumor regions and quantify the degree of spatial heterogeneity. Let D = d1,d2,…,dn be the Shannon index for n regions in a tumor. We used Gaussian mixture models to fit data D: D SK k¼1okNðmk; s2 kÞ: ð2Þ where μk, ,s2 k, and ωk are the mean, variance, and weight of a Gaussian distribution k, and K is the number of clusters. The Bayesian information criterion was then used to select the best number of clusters K [18]. We used K = 1–5 as the range of K to avoid small EDI groups (S1 Text). The final value of K thus is a measurement of heterogeneity and the score of EDI for a tumor.

Fig 5. The relationship between ecological heterogeneity and cancer genomic aberrations in 507 grade 3 tumors. (A) Genome-wide copy number aberrations in grade 3 breast tumors and genomic coordinates of genes with copy number aberrations enriched in the EDI-high group. Lengths of black lines denote level of enrichment significance with copy number gains (above the horizontal line) or losses (below the horizontal line). (B) Kaplan–Meier curves illustrating the duration of disease-specific survival in grade 3 breast cancer patients according to copy number loss of the 4p14 region (left) and the EDI-high group with additional information of 4p14 copy number loss (right). (C) Kaplan–Meier curves illustrating the duration of disease-specific survival according to copy number loss of the 5q13 region (left) and the EDI-high group with additional information of 5q13 copy number loss (right).

http://dx.doi.org:/10.1371/journal.pmed.1001961.g005

This study has a number of limitations. The motivation for our computational development was to use a data-driven model and measure the degree of spatial heterogeneity in tumor pathological specimens. In this model, only three major cell types in breast tumors were considered. Further sub-classification of the different types of stromal and immune cells by immunohistochemistry may add additional discriminatory value to our model. For dissecting spatial heterogeneity, we chose to use square regions with equal sizes. We found that EDI was correlated with the size of the region chosen for calculation of the Shannon diversity index, and as such the spatial heterogeneity is scale dependent. This phenomenon has been well described in a number of studies in ecology that show that a scale needs to be chosen that is appropriate for the ecological process under study [38,39], further highlighting the analogy between tumor studies and ecology. Similar to the recent observation that breast cancer subclonal heterogeneity is correlated with tumor size [35], we also found an association between microenvironmental heterogeneity and tumor size; hence, EDI may have more limited value in smaller tumors. However, small tumors were present in the EDI-high group, and addition of EDI within tumors grouped by size further stratified their prognosis. We found that EDI was prognostic only in grade 3 tumors in our study, which could be a limitation, given the possible discordance in grading between pathologists.

The identification of additional biomarkers in subgroups of patients that identify them as high risk is important for patient management and to avoid overtreatment for low-risk patients. We envision that the use of our measure of microenvironment heterogeneity, together with key genomic alterations, will enable the diagnosis of patients at very high risk of relapse and facilitate the enrollment of these patients into additional clinical trials for novel therapies or treatment intensification. Our novel computational approach provides a fully automated tool that is relatively easy to implement. Integration of this measure with genomic profiling provides additional prognostic information independent of known clinical parameters. The results of this study highlight the possibility of a grade-3-specific prognostic tool that may aid in further classification of high-grade breast cancer patients beyond standard assays such as ER and HER2 status.

 

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Reengineering Therapeutics

Posted in Biological Networks, BioTechnology - Venture Creation, Cancer and Current Therapeutics, Cell Biology, Signaling & Cell Circuits, CRISPR/Cas9 & Gene Editing, Curation, Disease Biology, Genome Biology, Innovations, Metabolism, Proteins, Proteomics, tagged CRISPR/Cas9 modification, synNotch pathways on February 6, 2016| Leave a Comment »

Reengineering Therapeutics

Larry H. Bernstein, MD, FCAP, Curator

LPBI

The synNotch solution: UCSF scientists engineer a next-gen T-cell immunotherapy

Sunday, January 31, 2016 | By John Carroll

2.2.9   Reengineering Therapeutics, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

CAR-T has been all the rage in cancer R&D for several years now as a slate of biotech upstarts pursue highly promising work reengineering T cells into attack weapons by adding a chimeric antigen receptor that can zero in on particular cancer cells. The approach has been highly effective in acute lymphoblastic leukemia, triggering an attack on B cells by homing in on the CD19 antigen, a breakthrough that has inspired a race to the regulatory finish line with the first CAR-Ts.

That approach, though, has run into some major obstacles when researchers move from the blood cancer to solid tumors. But now a group of scientists working with UC San Francisco’s Wendell Lim say they’ve come up with a new therapeutic model for T-cell engineering that promises to overcome that hurdle and make it a more precise weapon that can tackle solid tumors while avoiding off-target reactions that threaten patients.

The key to this new approach is a new receptor: synNotch. Taking a cue from nature, which relies on a sensor called Notch to perform key functions, the synthetic biology engineers say they can add a receptor that includes one section that sticks out from the cell with one that lies inside. By tinkering with synNotch they can reengineer the immune cell to run down a particular cancer cell target and then issue instructions to turn genes on or off to set up the other half of the therapeutic equation.

In a project described in Cell, the team says they created a synNotch that recognized an antigen on the surface of the cancer cell while the internal mechanism contributed a chimeric antigen receptor that recognized a different antigen. They then tested it on a mouse model that included two different tumor cells: one with both targets recognized by the external synNotch sensor and the CAR and one with just the CAR target.

The newly programmed attack weapon zeroed in on the two targets (which required synNotch activation for it to work) while leaving the other alone, providing preclinical proof-of-concept evidence that they could create a much more efficient tumor cell killing vehicle.

“The kinds of engineered T cells that we can now construct give us the exciting potential to create precision cancer therapeutics that take advantage of all the genomic and proteomic information we are currently gathering on disease,” said Lim, the senior author of the study. “This genomic information now becomes actionable.”

The team was led by Leonardo Morsut and Kole Roybal.

Lim added that it is possible to reengineer a T cell with multiple synNotches to make it even more precise. And there are added applications for autoimmune disease, regenerative medicine, and more.

Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors

Leonardo  Morsut, Kole T. Roybal, Xin Xiong, Russell M. Gordley, Scott M. Coyle, Matthew Thomson, Wendell A. Lim

J. Cell 2016     http://dx.doi.org/10.1016/j.cell.2016.01.012

http://www.cell.com/cms/attachment/2045482108/2056813637/fx1.jpg

• •SynNotch receptors with altered extra- and intracellular domains yield new responses
• •SynNotch pathways drive diverse user-defined responses in many mammalian cell types
• •Multiple synNotch pathways are functionally orthogonal to one another
• •SynNotch pathways control differentiation, spatial patterning, and Boolean decisions

The Notch protein is one of the most mechanistically direct transmembrane receptors—the intracellular domain contains a transcriptional regulator that is released from the membrane when engagement of the cognate extracellular ligand induces intramembrane proteolysis. We find that chimeric forms of Notch, in which both the extracellular sensor module and the intracellular transcriptional module are replaced with heterologous protein domains, can serve as a general platform for generating novel cell-cell contact signaling pathways. Synthetic Notch (synNotch) pathways can drive user-defined functional responses in diverse mammalian cell types. Because individual synNotch pathways do not share common signaling intermediates, the pathways are functionally orthogonal. Thus, multiple synNotch receptors can be used in the same cell to achieve combinatorial integration of environmental cues, including Boolean response programs, multi-cellular signaling cascades, and self-organized cellular patterns. SynNotch receptors provide extraordinary flexibility in engineering cells with customized sensing/response behaviors to user-specified extracellular cues.

Tricked-Out Immune Cells Could Attack Cancer, Spare Healthy Cells  

New Cell-Engineering Technique May Lead To Precision Immunotherapies

By Pete Farley on January 28, 2016

https://www.ucsf.edu/news/2016/01/401471/tricked-out-immune-cells-could-attack-cancer-spare-healthy-cells

UC San Francisco scientists have created a new class of highly customizable biological sensors that can be used to form “logic gates” inside cells of the immune system, giving these cells the capability to home in on and kill a wide range of cancer cells while preventing them from attacking normal tissue.

As reported in two companion papers published Jan. 28 in the online edition of Cell, in addition to their potential to bring much-needed precision and safety to the form of cancer immunotherapy known as CAR T cell therapy, these versatile new sensors, known as synNotch receptors, can also be inserted into cells such as nerve and muscle cells. The receptors may have uses in regenerative medicine, in the treatment of autoimmune diseases, and in basic biological research.

“SynNotch receptors provide us with one of the most flexible ways we have to reprogram the behavior and function of almost any cell,” said Wendell A. Lim, PhD, chair and professor of cellular and molecular pharmacology at UCSF, and senior author of the two new papers. “One of the most exciting applications is in engineering therapeutic cells – we can now provide these cells with highly precise instructions about how to recognize and respond to disease.”

Gene therapy pioneer James Wilson uses CRISPR/Cas9 to target liver disease

Wednesday, February 3, 2016 | By John Carroll

UPenn’s James Wilson

One of the pioneers in the whole gene therapy movement of the past 35 years has combined his knowledge of viral vectors with the hot new CRISPR/Cas9 tech to tackle a rare genetic liver disease. And his work with rodents highlighted both the promise of this new technology as well as an unexpected hurdle.

James Wilson at the University of Pennsylvania is virtually the father of adeno-associated virus–or AAV–vectors used to deliver gene therapies. After years of up and down progress, including an early patient death that slowed research in gene therapies for decades, his technology was in-licensed by ReGenX, which has since outlicensed it to a group of biotechs pursuing new gene therapy programs.

In what is described as a first in research circles, he used an AAV vector to deliver the components of CRISPR/Cas9 gene editing tools into a mouse model of a rare metabolic urea-cycle disorder, triggered by a deficiency in the ornithine transcarbamylase (OTC) enzyme.  When one of a series of enzymes is missing or “deficient,” ammonia can accumulate in the blood and circulate into the brain, where it can badly damage brains. OTC deficiency occurs in one in every 40,000 births.

Wilson’s group used one AAV to deliver a Cas9 enzyme–the cutting tool–specifically into liver cells. Another vector carried a guide RNA to the specified spot and donor DNA to correct the mutation in a cut-and-paste approach that is spreading around academic labs like wild fire.

Wilson says his team achieved a 10% reversion in the liver cells of newborn mice, with an increased survival rate for challenged rodents and a high death rate in the untreated group of newly born mice. In adult mice, though, the team say that the experiment didn’t work as planned, highlighting a needed correction in the process. And now they’re following up with new approaches to see how that might work.

“Correcting a disease-causing mutation following birth in this animal model brings us one step closer to realizing the potential of personalized medicine,” said Wilson, a professor of medicine and director of the Orphan Disease Center at Penn. “Nevertheless, my 35-year career in gene therapy has taught me how difficult translating mouse studies to successful human treatments can be. From this study, we are now adjusting the gene-editing system in the next phases of our investigation to address the unforeseen complications seen in adult animals.”

New CRISPR/Cas9 delivery method could offer a clinical pathway

February 2, 2016 | By Michael Gibney

CRISPR/Cas9 gene editing is a rapidly developing technique that is thought to provide revolutionary new ways to manipulate genes for the treatment of a number of diseases. Delivering the CRISPR therapeutic in an efficient, safe and predictable way, though, has been difficult–to this end, researchers at UMass have created a means of administering the gene editor that could help send it to clinical trials.

CRISPR/Cas9 is a natural immune system in bacteria used to protect them from foreign genetic material, and scientists have used its components to cut and repair DNA sequences to replace faulty, disease-causing portions with corrected versions.

The difficulty comes about in getting the separate components (the Cas9 “scalpel,” the DNA repair template and an RNA guide) to the genetic material in a target cell. Previous attempts at delivering the system through disruptive, high-powered injection has caused damage to the liver and required too much volume when treating mice with metabolic diseases.

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Signaling of Immune Response in Colon Cancer

Posted in BioIT: BioInformatics, Biological Networks, Biomarkers & Medical Diagnostics, Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Curation, Cytokines, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Gastroenterology, Gene Regulation, Human Immune System in Health and in Disease, Immuno-Oncology & Genomics, Immunology, Metabolism, Metabolomics, Proteomics, tagged Colorectal cancer, protein, STING (innate immune signaling) on January 9, 2016| Leave a Comment »

Signaling of Immune Response in Colon Cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Revised 1/13/2016

STING Protein May Serve as Biomarker for Colorectal and Other Cancers

http://www.genengnews.com/gen-news-highlights/sting-protein-may-serve-as-biomarker-for-colorectal-and-other-cancers/81252165/

 

Scientists at University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center say they have discovered how the stimulator of interferon genes (STING) signaling pathway may play an important role in alerting the immune system to cellular transformation. They believe their finding will shed further light on the immune system’s response to cancer development.

In 2008, Glen N. Barber, Ph.D., leader of the viral oncology program at Sylvester, and professor and chairman of cell biology at the Miller School of Medicine, and colleagues published in Nature (“STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling”) the discovery of STING as a new cellular molecule that recognizes virus and bacteria infection to initiate host defense and immune responses. In the new study, published in Cell Reports (“Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis”), they describe STING’s role in the potential suppression of colorectal cancer.

“Since 2008 we’ve known that STING is crucial for antiviral and antibacterial responses,” said Dr. Barber. “But until now, little had been known about its function in human tumors. In this study we show, for the first time, that STING signaling is repressed in colorectal carcinoma and other cancers, an event which may enable transformed cells to evade the immune system.”

Colorectal cancer currently affects around 1.2 million people in the U.S. and 150,000 new cases are diagnosed every year, making it the third most common cancer in both men and women. Since most colon cancers develop from benign polyps, they can be treated successfully when detected early. However, if the tumor has already spread, survival rates are generally low.

Using disease models of colorectal cancer, the team of Sylvester scientists showed that loss of STING signaling negatively affected the body’s ability to recognize DNA-damaged cells. In particular, certain cytokines that facilitate tissue repair and antitumor priming of the immune system were not sufficiently produced to initiate a significant immune response to eradicate the colorectal cancer.

“We were able to show that impaired STING responses may enable damaged cells to elude the immune system,” continued Dr. Barber. “And if the body doesn’t recognize and attack cancer cells, they will multiply and, ultimately, spread to other parts of the body.”

He and his colleagues suggest evaluating STING signaling as a prognostic marker for the treatment of colorectal as well as other cancers. For example, Dr. Barber’s study showed that cancer cells with defective STING signaling were particularly prone to attack by oncolytic viruses presently being used as cancer therapies.

“Impaired STING responses may enable damaged cells to evade host immunosurveillance processes, although they provide a critical prognostic measurement that could help predict the outcome of effective oncoviral therapy,” wrote the investigators.

STING Protein Could be Used for Cancer Diagnosis

http://www.technologynetworks.com/Proteomics/news.aspx?ID=186674

 

This is the first detailed examination of how the stimulator of interferon genes (STING) signaling pathway, discovered by Glen N. Barber, Ph.D., Leader of the Viral Oncology Program at Sylvester Comprehensive Cancer Center, may play an important role in alerting the immune system to cellular transformation.

In 2008, Barber, who is also Professor and Chairman of Cell Biology at the University of Miami Miller School of Medicine, and colleagues published in Nature the discovery of STINGas a new cellular molecule that recognizes virus and bacteria infection to initiate host defense and immune responses. In the new study they describe STING’s role in the potential suppression of colorectal cancer.

“Since 2008 we’ve known that STING is crucial for antiviral and antibacterial responses,” said Barber. “But until now, little had been known about its function in human tumors. In this study we show, for the first time, that STING signaling is repressed in colorectal carcinoma and other cancers, an event which may enable transformed cells to evade the immune system.”

Colorectal cancer currently affects around 1.2 million people in the United States and 150.000 new cases are diagnosed every year, making it the third most common cancer in both men and women. Since most colon cancers develop from benign polyps, they can be treated successfully when detected early. However, if the tumor has already spread, survival rates are generally low.

Using disease models of colorectal cancer, the team of Sylvester scientists showed that loss of STING signaling negatively affected the body’s ability to recognize DNA-damaged cells. In particular, certain cytokines – small proteins important for cell signaling – that facilitate tissue repair and anti-tumor priming of the immune system were not sufficiently produced to initiate a significant immune response to eradicate the colorectal cancer.

“We were able to show that impaired STING responses may enable damaged cells to elude the immune system,” added Barber. “And if the body doesn’t recognize and attack cancer cells, they will multiply and, ultimately, spread to other parts of the body.”

Barber and his colleagues suggest evaluating STING signaling as a prognostic marker for the treatment of colorectal as well as other cancers. For example, Barber’s study showed that cancer cells with defective STING signaling were particularly prone to attack by oncolytic viruses presently being used as cancer therapies. Alternate studies with colleagues have also shown that activators of STING signaling are potent stimulators of anti-tumor immune responses. Collectively, the control of STING signaling may have important implications for cancer development as well as cancer treatment.

 

Every step you take: STING pathway key to tumor immunity

http://sciencelife.uchospitals.edu/2014/11/20/every-step-you-take-sting-pathway-key-to-tumor-immunity/

A recently discovered protein complex known as STING plays a crucial role in detecting the presence of tumor cells and promoting an aggressive anti-tumor response by the body’s innate immune system, according to two separate studies published in the Nov. 20 issue of the journal Immunity.

The studies, both from University of Chicago-based research teams, have major implications for the growing field of cancer immunotherapy. The findings show that when activated, the STING pathway triggers a natural immune response against the tumor. This includes production of chemical signals that help the immune system identify tumor cells and generate specific killer T cells. The research also found that targeted high-dose radiation therapy dials up the activation of this pathway, which promotes immune-mediated tumor control.

These findings could “enlarge the fraction of patients who respond to immunotherapy with prolonged control of the tumor,” according to a commentary on the papers by the University of Verona’s Vincenzo Bronte, MD. “Enhancing the immunogenicity of their cancers might expand the lymphocyte repertoire that is then unleashed by interference with checkpoint blockade pathways,” such as anti-PD-1.

STING, short for STimulator of INterferon Genes complex, is a crucial part of the process the immune system relies on to detect threats — such as infections or cancer cells — that are marked by the presence of DNA that is damaged or in the wrong place, inside the cell but outside the nucleus.

Detection of such “cytosolic” DNA initiates a series of interactions that lead to the STING pathway. Activating the pathway triggers the production of interferon-beta, which in turn alerts the immune system to the threat, helps the system detect cancerous or infected cells, and ultimately sends activated T cells into the battle.

“We have learned

“Innate immune sensing via the host STING pathway is critical for tumor control by checkpoint blockade,” Gajewski’s team noted in their paper. They found promising drugs known as checkpoint inhibitors — such as anti PD-1 or anti PD-L1, which can take the brakes off of an immune response — were not effective in STING-deficient mice. New agents that stimulate the STING pathway are being developed as potential cancer therapeutics.

A second University of Chicago team, led by cancer biologistYang-Xin Fu, MD, PhD, professor of pathology, and Ralph Weichselbaum, MD, chairman of radiation and cellular oncology and co-director of the Ludwig Center for Metastasis Research, found that high-dose radiation therapy not only kills targeted cancer cells but the resulting DNA damage drives a systemic immune response.

a great deal recently about what we call checkpoints, the stumbling blocks that prevent the immune system from ultimately destroying cancers,” said Thomas Gajewski, MD, PhD, professor of medicine and pathology at the University of Chicago and senior author of one of the studies. “Blockade of immune checkpoints, such as with anti-PD-1, is therapeutic in a subset of patients, but many individuals still don’t respond. Understanding the role of the STING pathway provides insights into how we can ‘wake up’ the immune response against tumors. This can be further boosted by checkpoint therapies.”

The two published studies, he said, help move this approach forward.

In a series of experiments in mice, both research teams found tumor cell-derived DNA could initiate an immune response against cancers. But when tested in mice that lacked a functional gene for STING, the immune system did not effectively respond.

“This result unifies traditional studies of DNA damage with newly identified DNA sensing of immune responses,” Fu said.

“This is a previously unknown mechanism,” Weichselbaum added.

In mice that lacked STING, however, there was no therapeutic immune response. The induction of interferons by radiation and consequent cancer cell killing, they conclude, depends on STING-pathway signaling.

They did find that combining cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an earlier step in the STING pathway, with radiation, could greatly enhance the antitumor efficacy of radiation.

“This opens a new avenue to develop STING-related agonists for patients with radiation-resistant cancers,” Fu said.

 

 

STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors

Seng-Ryong Woo¹, Mercedes B. Fuertes¹, Leticia Corrales¹, …., Maria-Luisa Alegre², Thomas F. Gajewski^{1, 2}   

Immunity 20 Nov 2014; 41(5): 830–842    http://dx.doi.org:/10.1016/j.immuni.2014.10.017

 

Highlights

• Spontaneous T cell responses against tumors require the host STING pathway in vivo

• Tumor-derived DNA can induce type I interferon production via STING

• Tumor DNA can be identified in host APCs in the tumor microenvironment in vivo

---

Summary

Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8⁺ T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-β production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-β production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.

 

http://ars.els-cdn.com/content/image/1-s2.0-S1074761314003938-fx1.jpg

 

Immunity Erratum STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors

Seng-Ryong Woo, Mercedes B. Fuertes, Leticia Corrales, Stefani Spranger, Michael J. Furdyna, Michael Y.K. Leung, Ryan Duggan, Ying Wang, Glen N. Barber, Katherine A. Fitzgerald, Maria-Luisa Alegre, and Thomas F. Gajewski* *Correspondence: tgajewsk@medicine.bsd.uchicago.edu http://dx.doi.org/10.1016/j.immuni.2014.12.015 (Immunity 41, 830–842; November 20, 2014)

The original Figure 3C accidentally contained a duplicated panel in the bright-field column, third row down, and this has now been replaced with the correct data. The change does not alter the conclusions of the paper. This mistake has now been corrected online, and the authors regret the error.

 

Cytosolic DNA Sensors (CDSs): a STING in the tail – Review

November 2012   http://www.invivogen.com/review-cds-ligands

The innate immune system provides the first line of defense against infectious pathogens and serves to limit their early proliferation. It is also vital in priming and activating the adaptive immune system.

Innate immune detection of intracellular DNA derived from viruses and invasive bacteria is important to initiate an effective protective response. This crucial step depends on cytosolic DNA sensors (CDSs), which upon activation trigger the production of type I interferons (IFNs) and the induction of IFN-responsive genes and proinflammatory chemokines.
Although the identity of these CDSs is not fully uncovered, much progress has been made in understanding the signaling pathways triggered by these sensors.

Cytosolic DNA-mediated production of type I IFNs (mainly IFN-β) requires the transcription factor IFN regulatory factor 3 (IRF3), which is activated upon phosphorylation by TANK-binding-kinase-1 (TBK1) [1].

STING in DNA sensing

Recently, a new molecule, STING (stimulator of IFN genes), has been shown to be essential for the TBK1-IRF3- dependent induction of IFN-β by transfected DNA ligands and intracellular DNA produced by pathogens after infection [2, 3].
STING (also known as MITA, MPYS and ERIS) is a transmembrane protein that resides in the endoplasmic reticulum (ER) [2-6]. In response to cytosolic DNA, STING forms dimers and translocates from the ER to the Golgi then to punctate cytosolic structures where it colocalizes with TBK-1, leading to the phosphorylation of IRF3.
How STING stimulates TBK1-dependent IRF3 activation was recently elucidated by Tanaka and Chen. They found that, upon cytosolic DNA sensing, the C-terminal tail of STING acts as a scaffold protein to promote the phosphorylation of IRF3 by TBK1 [7].

STING in the host response to intracellular pathogens. Linking type I IFN response and autophagy for better defense

http://www.invivogen.com/images/STING-autophagy.png

 

STING activates the IFN response

Until very recently, STING in addition to its role as an adaptor protein was also thought to function as a sensor of cyclic dinucleotides.
Burdette et al. first demonstrated that STING binds directly to the bacterial molecule cyclic diguanylate monophosphate (c-di-GMP) [8]. This finding was confirmed by several teams who examined the structure of STING bound to c-di-GMP [9-11], including Cheng and colleagues, however their data suggest that STING is not the primary sensor of c-di-GMP [12]. Rather, they indicate that DDX41, an identified CDS, functions as a direct receptor for cyclic dinucleotides upstream of STING. The authors hypothesized that DDX41 binds to c-di-GMP then forms a complex with STING to activate the IFN response.

STING induces autophagy

Exciting new developments reveal that STING participates in another aspect of innate immunity, autophagy.
Autophagy plays a critical role in host defense responses to pathogens by promoting the elimination of microbes that enter into the cytosol by their sequestration into autophagosomes and their delivery to the lysosome.

 

http://www.invivogen.com/images/STING-CDS_pathway_small.jpg

Recent studies have reported that DNA viruses and intracellular bacteria induce autophagy and that this process is dependent on cytosolic genomic DNA and STING [13-15]. Robust induction of autophagy was also observed after transfection of various double stranded (ds) DNA species, such as poly(dA:dT), poly(dG:dC) or plasmid DNA, but not single stranded (ss) DNA, dsRNA or ssRNA [16].

Interestingly, activated STING was shown to relocate to unidentified membrame-bound compartments where it colocalizes with LC3, a hallmark of autophagy, and ATg9a. The latter protein was reported to regulate the interaction between STING and TBK1 after dsDNA stimulation [16]. The E3 ubiquitin ligases TRIM56 and TRIM32
were also found to regulate STING by mediating its dimerization through K63-linked ubiquitination [17, 18].

Several cytosolic DNA sensors upstream of STING have been proposed.
DNA-dependent activator of IRFs (DAI) was the first CDS discovered based on the ability of transfected poly(dA:dT) to induce IFN-β [19]. However, the role of DAI has been shown to be very cell-type specific and cells derived from DAI-deficient mice responded normally to dsDNA ligands [20].

While analyzing immune responses to dsDNA regions derived from vaccinia virus (VACV-70) or Herpes simplex virus 1 (HSV-60) genomes, Unterholzner et al. identified IFI16 as a DNA binding protein mediating IFN-β induction [21]. Interestingly, IFI16 belongs to a new family of pattern recognition receptors that contain the pyrin and HIN domain (PYHIN), termed AIM2-like receptors (ALRs).

AIM2 is a STING-independent cytosolic DNA sensor that forms an inflammasome with ASC to trigger caspase-1 activation and the secretion of the proinflammatory cytokines IL-1β and IL-18 [20].

Members of the DExD/H-box helicase superfamily have also been reported to function as cytosolic DNA sensors. While DHX36 and DHX9 were identified as STING-independent but MyD88-dependent sensors of CpG-containing DNA in plasmacytoid dendritic cells, DDX41 was found to bind various dsDNA ligands and localize with STING to promote IFN-β expression [22]. Other CDSs have been reported to function independently of STING: RNA Pol III, LRRFIP1 and Ku70 [20].

Unlike cytosolic RNA sensors (RIG-I, MDA-5), which detect structural moieties specific to pathogen RNA, such as 5’-triphosphates, it is not clear whether cytosolic DNA sensors can recognize any particular structural motif of DNA that would discriminate between self and non-self. This suggests that CDSs may have a role not only in anti-microbial innate immune responses but also in autoimmunity. A multitude of CDSs have been described but whether they are all true receptors remains an open question.

1. Stetson DB & Medzhitov R. 2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity. 24(1):93-103.
2. Ishikawa H. & Barber GN., 2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 455(7213):674-8.
3. Ishikawa H. et al., 2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 461(7265):788-92.
4. Zhong B. et al., 2008. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 29(4):538-50.
5. Jin L. et al., 2008. MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals. Mol Cell Biol. 28(16):5014-26.

 

UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1).

Kemp MG¹, Lindsey-Boltz LA², Sancar A³. Author information

 J Biol Chem. 2015 May 8;290(19):12184-94.  http://dx.doi.org:/10.1074/jbc.M115.649301. Epub 2015 Mar 19.

The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders.

 

 

STING and the innate immune response to nucleic acids in the cytosol

Dara L Burdette & Russell E Vance

https://mcb.berkeley.edu/labs/vance/Resources/Burdette%20(2013)%20review.pdf

Cytosolic detection of pathogen-derived nucleic acids is critical for the initiation of innate immune defense against diverse bacterial, viral and eukaryotic pathogens. Conversely, inappropriate responses to cytosolic nucleic acids can produce severe autoimmune pathology. The host protein STING has been identified as a central signaling molecule in the innate immune response to cytosolic nucleic acids. STING seems to be especially critical for responses to cytosolic DNA and the unique bacterial nucleic acids called ‘cyclic dinucleotides’. Here we discuss advances in the understanding of STING and highlight the many unresolved issues in the field.

The detection of pathogen-derived nucleic acids is a central strategy by which the innate immune system senses microbes to then initiate protective responses1. Conversely, inappropriate recognition of self nucleic acids can result in debilitating autoimmune diseases such as systemic lupus erythematosus2. It is therefore important to understand the molecular basis of the detection of nucleic acids by the innate immune system. Studies have established that nucleic acids derived from extracellular sources are sensed mainly by endosomal Toll-like receptors (TLRs), such as TLR3, TLR7 and TLR9, whereas cytosolic nucleic acids are detected independently of TLRs by a variety of less-well-characterized mechanisms1.

Studies have identified STING (‘stimulator of interferon genes’; also known as TMEM173, MPYS, MITA and ERIS) as a critical signaling molecule in the innate response to cytosolic nucleic-acid ligands. STING was first described as a protein that interacts with major histocompatibility complex class II molecules3, but the relevance of this interaction remains unclear. Subsequent studies have instead focused on the role of STING in the transcriptional induction of type I interferons and coregulated genes in response to nucleic acids in the cytosol. Several groups have independently isolated STING by screening for proteins able to induce interferon-B (IFN-B) when overexpressed4–6. Studies of STING-deficient mice have subsequently confirmed the essential role of STING in innate responses to cytosolic nucleic-acid ligands, particularly double-stranded DNA (dsDNA) and unique bacterial nucleic acids called ‘cyclic dinucleotides’7–9. Several studies have also linked STING to the interferon response to cytosolic RNA5–7, but this has not been found consistently7,8,10,11; thus, we focus here on the role of STING in response to DNA and cyclic dinucleotides.

 

Protein Stimulator of interferon genes protein

Gene TMEM173

Organism Homo sapiens (Human)

Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway. Essential for the induction of IFN-beta in response to human herpes simplex virus 1 (HHV-1) infection. Exhibits 2′,3′ phosphodiester linkage-specific ligand recognition. Can bind both 2′-3′ linked cGAMP and 3′-3′ linked cGAMP but is preferentially activated by 2′-3′ linked cGAMP (PubMed:26300263)

Stimulator of interferon genes protein (IPR029158)

Transmembrane protein 173, also known as stimulator of interferon genes protein (STING) or endoplasmic reticulum interferon stimulator (ERIS), is a transmembrane adaptor protein which is involved in innate immune signalling processes. It induces expression of type I interferons (IFN-alpha and IFN-beta) via the NF-kappa-B and IRF3, pathways in response to non-self cytosolic RNA and dsDNA [PMID: 18724357, PMID: 19776740,PMID: 18818105, PMID: 19433799].

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