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Posts Tagged ‘modulation of tumor tolerance’


Tumor Associated Macrophages: The Double-Edged Sword Resolved?

Writer/Curator: Stephen J. Williams, Ph.D.

Cell-based immunity is vital for our defense against pathologic insult but recent evidence has shown the role of cell-based immunity, especially macrophages to play an important role in both the development and hindrance of tumor growth, including role in ovarian, hematologic cancers, melanoma, and breast cancer.  In the past half century, new immunological concepts of cancer initiation and progression have emerged, including the importance of the harnessing the immune system as a potential anti-cancer strategy. However, as our knowledge of the immune system and tumor biology has grown, the field has realized an immunological conundrum: how can an immune system act to both prevent tumor growth and promote the tumor’s growth?

As discussed in the lower section of this post, authors of a paper in the journal Science show how different populations of tumor-associated macrophages (TAMs) may exert both positive and negative effects on tumor cells, producing a sort of ying-yang war between the tumor and the immune system.

The Immune System: Brief Overview and Role in Cancer

celllineageimmunesystem

 

 

 

 

Figure. Cell lineage of the immune system. A description of the different cell types can be found here.

 

 

 

 

 

 

Histologic evaluation of multiple tumor types, especially solid tumors, reveal the infiltration of diverse immunological cell types, including myeloid and lymphoid cell lineages, such as macrophages and NK, T cell and B cells respectively.

The immunological conundrum

immuncecancerconundrum

 

Figure. Potential inflammatory signaling pathways in breast cancer stem cells.
Breast cancer stem cells may be regulated by chemokine- and/or cytokine-mediated inflammatory signaling in an autocrine or paracrine manner. (from University of Tokyo at http://www.ims.u-tokyo.ac.jp/system-seimei/en/research2_e.htm)

 

Role of Tumor Associated Macrophages

There are conflicting reports as to the functional consequence of these infiltrating tumor-associated macrophages (TAMs). TAMs have been shown to secrete mediators such as interleukins and cytokines in a paracrine manner such as CCL2, IL10 and TGFβ. In certain instances these cytokines and mediators actually promote the growth of the surrounding tumors.

J Leukoc Biol 2009 Nov 86(5) 1065-73, Figure 1

 

 

 

Figure.  TAMs can be divided into subpopulations with distinctive functions and secretogogues.

 

For Further Reference

Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. http://www.ncbi.nlm.nih.gov/pubmed/23089461 anti-inflamm IL10 and TGFB

Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner

TAMscytokines

 

Figure 2: TAM functions in tumor progression. Tumor cells and stromal cells, which produce a series of chemokines and growth factors, induce monocytes to differentiate into macrophages. In the tumor, most macrophages are M2-like, and they express some cytokines, chemokines, and proteases, which promote tumor angiogenesis, metastasis, and immunosuppression. From Macrophages in Tumor Microenvironments and the Progression of Tumors

 

 

 

 

 

 

ICB-14-NC-BRONTE-V2

Macrophages integrate metabolic and environmental signals to promote tumor growth. Area within dotted rectangle indicates proposed mechanisms of action. ARG, arginase; HIF, hypoxia-inducible factor; MCT, monocarboxylate transporter; NADH, nicotine adenine dinucleotide, reduced; PKM2, M2 isoform of pyruvate kinase; VEGF, vascular endothelial growth factor from Tumor cells hijack macrophages via lactic acid adapted from Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature (e-pub ahead of print 13 July 2014; doi:10.1038/nature13490). | Article |

Depletion of M2-Like Tumor-Associated Macrophages Delays Cutaneous T-Cell Lymphoma Development In Vivo

Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma

Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration

Tumor-Associated Macrophages Regulate Murine Breast Cancer Stem Cells Through a Novel Paracrine EGFR/Stat3/Sox-2 Signaling Pathway

Science Paper: Different Populations of TAMS Have Different Tumor Effects

The cellular and molecular origin of tumor-associated macrophages Eric G. Pamer1 Ruth A. Franklin1,2, Will Liao3, Abira Sarkar1, Myoungjoo V. Kim1,2, Michael R. Bivona1, Kang Liu4, Ming O. Li1, Science 23 May 2014: Vol. 344 no. 6186 pp. 921-925

A recent Science paper from Cornel has investigated the origin, function, and characterization of TAMs on breast cancer growth. In summary, their efforts and research suggest different populations of TAMs with varied tumorigenic effects, a finding which may help explain the immunologic conundrum with respect to solid tumors.

The authors characterized the infiltrating immune cell types in a MMTV-PyMt model of breast cancer.

 

The MMTV-PyMt mouse breast cancer model:

is a transgenic model where mammary gland expression of the polyoma middle T antigen (PyMT) is driven by the Mouse Mammary Tumor Virus promoter (MMTV).

Microbiol. Mol. Biol. Rev. 2009 Sep 73(3) 542-63, FIG. 5

 

 

 

 

 

 

 

 

 

For a review of mouse models of breast cancer please see

Mouse models of breast cancer metastasis. Anna Fantozzi1 and Gerhard Christofori. Breast Cancer Res. 2006; 8(4): 212.

 

Results

1.     Macrophages constitute the predominate myeloid cell population in MMTV-PyMT mammary tumors

Tumor infiltrating immune cells included

  • Myeloid cells comprised 50% of CD45+ infiltrating leukocytes.
  • The CD45 antigen, also known as Protein tyrosine phosphatase, receptor type, C (PTPRC) is an enzyme that, in humans, is encoded by the PTPRC gene, and acts as a regulator of B and T-lymphocytes.
  • Authors noted three types of cells classified as Type I, II, and III based on
  1. Cell morphology
  2. Major histocompatibility complex
  • Infiltrating monocytes and neutrophils
  • Cells with dendritic and macrophage markers

 

2. TAMS differentiate from CCR2+ inflammatory monocytes

  • To determine whether Ly6C+CCR2+ inflammatory monocytes contributed to TAMs and MTMs, authors crossed PyMT mice to Ccr2−/− mice and found MTMs (mammary tumor macrophages) were significantly reduced in Ccr2−/− PyMT mice, implying that MTMs are constitutively repopulated by inflammatory monocytes
  • To determine whether inflammatory monocytes were required for TAM maintenance, we generated CCR2DTR PyMT mice expressing diphtheria toxin receptor (DTR) under control of the Ccr2 locus DT treatment resulted in 96% depletion of tumor-associated monocytes compared to 80% depletion in Ccr2−/− mice
  • To investigate whether monocytes could differentiate into TAMs in vivo, we transferred CCR2+ bone marrow cells isolated from CCR2GFP reporter mice into congenically marked CCR2DTR PyMT mice depleted of endogenous monocytes, we observed transferred cells in developing tumors demonstrate that tumor growth induces the differentiation of CCR2+ monocytes into TAMs.

 

3.     TAMs are phenotypically distinct from AAMs (M2 or alternatively activated macrophages)

  • Gene-expression profiling revealed the integrin CD11b (Itgam) was expressed at lower levels in TAMs than in MTMs while several other integrins and the integrin receptor Vcam1 were up-regulated in TAMs
  • AM population did not express AAM markers such as Ym1, Fizz1, and Mrc1; instead, MTMs more closely resembled AAMs. The authors detected Vcam1 up-regulation on TAMs as a late differentiation event

 

4.    RBPJ-dependent TAMs modulate the adaptive immune response

  • In DCs, canonical Notch signaling mediated by the key transcriptional regulator RBPJ controls lineage commitment and terminal differentiation. To explore whether Notch signaling played a role in TAM differentiation, authors used CD11ccre mice that efficiently deleted floxed DNA sequences to a greater extent in TAMs than MTMs, but not in monocytes or neutrophils (fig. S14). CD11ccreRbpjfl/fl PyMT mice exhibited a selective loss of MHCIIhiCD11blo TAMs ( 4A). However, a MHCIIhiCD11bhi population still remained
  • Transcriptional profiling comparing this population to WT TAMs confirmed a loss of the Notch-dependent program in RBPJ-deficient cells revealing that in the absence of RBPJ, inflammatory monocytes are unable to terminally differentiate into TAMs.

 

Other posts on this site on Immunology and Cancer include

The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Innovations in Tumor Immunology

T cell-mediated immune responses & signaling pathways activated by TLRs

Vaccines, Small Peptides, aptamers and Immunotherapy [9]

Report on Cancer Immunotherapy Market & Clinical Pipeline Insight

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

Immunotherapy in Cancer: A Series of Twelve Articles in the Frontier of Oncology by Larry H Bernstein, MD, FCAP

 

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