Abstract
Foxp3(+) regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3(+) T-bet(+) 'TH1-like' Tregs which are thymus-derived Helios(+) cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the TH1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69(+) Tregs are more suppressive than their CD69- counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site.
Keywords:
CD69; Immune response; Immunity; Immunology Section; T-bet; Treg; cancer; proliferation.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Biomarkers, Tumor / immunology
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Biomarkers, Tumor / metabolism
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Cell Proliferation* / drug effects
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Cells, Cultured
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Fibrosarcoma / chemically induced
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Fibrosarcoma / genetics
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Fibrosarcoma / immunology
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Fibrosarcoma / metabolism*
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Inflammation Mediators / immunology
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Inflammation Mediators / metabolism
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / immunology
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Interleukin-2 / metabolism*
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Lymphocyte Activation* / drug effects
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Lymphocytes, Tumor-Infiltrating / drug effects
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / metabolism*
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Methylcholanthrene
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Mice, Inbred C57BL
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Mice, Knockout
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Phenotype
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Sarcoma, Experimental / chemically induced
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Sarcoma, Experimental / genetics
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Sarcoma, Experimental / immunology
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Sarcoma, Experimental / metabolism*
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Signal Transduction
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T-Box Domain Proteins / deficiency
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism*
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism*
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Tumor Microenvironment
Substances
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Antibodies, Monoclonal
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Biomarkers, Tumor
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Inflammation Mediators
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Interleukin-2
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Methylcholanthrene