Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics.
Bottom Line: In our study, we utilized a mouse model of carcinogen-induced fibrosarcoma to examine the composition of tumor-infiltrating lymphocytes during tumor progression.In particular, we sought to determine whether CD4(+) Foxp3(+) regulatory T cells (Tregs) became enriched during tumor progression thereby contributing to tumor-driven immunosuppression.However, we found no evidence for antigen-driven migration of these T cells or for their participation in an antitumor immune response.
Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.Show MeSH
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Mentions: Fibrosarcomas were induced in mice approximately 80–150 days after injection of the carcinogen, MCA. The relative proportions of CD4+ Foxp3− and CD4+ Foxp3+ T cells among tumor‐infiltrating lymphocytes (TILs) were assessed and (Fig. 1a) there was a large range in Treg representation within the tumor‐infiltrating T‐cell pool (7–42%). The ratio of Foxp3− cells and Foxp3+ cells among CD4+ lymphocytes from disaggregated tumors (average, 4:1) was different from that observed in blood (average, 19:1, data not shown and Ref. 7), implying that these lymphocytes are tumor‐infiltrating cells and not simply blood‐borne contaminants. To further delineate the phenotype of these CD4+ T‐cell populations, a detailed phenotypic analysis of CD4+ TILs was performed. Distinct subpopulations of CD4+ T cells within the tumor were observed as defined by the expression of CD62L and CCR7. Although the majority of CD4+Foxp3+ T cells (Tregs) were CD62LloCCR7− and hence of an effector memory (Tem) phenotype (Figs. 1b and 1d), we found that on average less than half of the CD4+Foxp3− T cells were Tem cells (Figs. 1c and 1e). Notably, within the CD4+Foxp3− population, a significant number of cells expressed both CD62L and CCR7, markers compatible with a naïve or central memory T‐cell phenotype.8 Costaining with CD44 revealed low CD44 expression on the majority of the CD62Lhi TILs, supporting the premise that these cells are of a naïve phenotype (Fig. 1f and Supporting Information Fig. 1). This phenomenon contrasted with CD4+ T cells recovered from the lungs of influenza‐infected mice, where almost all were CD44hi, that is they have an activated phenotype. As expected, the majority of CD62LhiCD4+ T cells in the thymus have low CD44 expression indicative of a naïve phenotype (Supporting Information Fig. 1).
Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.