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Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics.

Ondondo B, Jones E, Hindley J, Cutting S, Smart K, Bridgeman H, Matthews KK, Ladell K, Price DA, Jackson DG, Godkin A, Ager A, Gallimore A - Int. J. Cancer (2013)

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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.

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A significant proportion of tumor‐infiltrating CD4+ T Cells are CD62LhiCCR7+CD44lo. Tumor‐cell suspensions were stained with CD4‐, Foxp3‐, CD62L‐ and CCR7‐specific monoclonal antibodies (mAbs) and analyzed by flow cytometry. Proportion of CD4+ cells that are Foxp3− or Foxp3+ are shown (a). Examples of CD62L and CCR7 staining on gated CD4+Foxp3+ and CD4+Foxp3− cells (b and c). Proportions of tumor‐infitrating CD4+Foxp3+and Foxp3− cells from spleens, tumors, draining and nondraining lymph nodes, represented as CD62LhiCCR7+, CD62LloCCR7+ and CD62LloCCR7− (d and e) (n = 7). Expression of CD44 by CD62Lhi and CD62Llo cells (f).
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ijc28556-fig-0001: A significant proportion of tumor‐infiltrating CD4+ T Cells are CD62LhiCCR7+CD44lo. Tumor‐cell suspensions were stained with CD4‐, Foxp3‐, CD62L‐ and CCR7‐specific monoclonal antibodies (mAbs) and analyzed by flow cytometry. Proportion of CD4+ cells that are Foxp3− or Foxp3+ are shown (a). Examples of CD62L and CCR7 staining on gated CD4+Foxp3+ and CD4+Foxp3− cells (b and c). Proportions of tumor‐infitrating CD4+Foxp3+and Foxp3− cells from spleens, tumors, draining and nondraining lymph nodes, represented as CD62LhiCCR7+, CD62LloCCR7+ and CD62LloCCR7− (d and e) (n = 7). Expression of CD44 by CD62Lhi and CD62Llo cells (f).

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).


Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics.

Ondondo B, Jones E, Hindley J, Cutting S, Smart K, Bridgeman H, Matthews KK, Ladell K, Price DA, Jackson DG, Godkin A, Ager A, Gallimore A - Int. J. Cancer (2013)

A significant proportion of tumor‐infiltrating CD4+ T Cells are CD62LhiCCR7+CD44lo. Tumor‐cell suspensions were stained with CD4‐, Foxp3‐, CD62L‐ and CCR7‐specific monoclonal antibodies (mAbs) and analyzed by flow cytometry. Proportion of CD4+ cells that are Foxp3− or Foxp3+ are shown (a). Examples of CD62L and CCR7 staining on gated CD4+Foxp3+ and CD4+Foxp3− cells (b and c). Proportions of tumor‐infitrating CD4+Foxp3+and Foxp3− cells from spleens, tumors, draining and nondraining lymph nodes, represented as CD62LhiCCR7+, CD62LloCCR7+ and CD62LloCCR7− (d and e) (n = 7). Expression of CD44 by CD62Lhi and CD62Llo cells (f).
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ijc28556-fig-0001: A significant proportion of tumor‐infiltrating CD4+ T Cells are CD62LhiCCR7+CD44lo. Tumor‐cell suspensions were stained with CD4‐, Foxp3‐, CD62L‐ and CCR7‐specific monoclonal antibodies (mAbs) and analyzed by flow cytometry. Proportion of CD4+ cells that are Foxp3− or Foxp3+ are shown (a). Examples of CD62L and CCR7 staining on gated CD4+Foxp3+ and CD4+Foxp3− cells (b and c). Proportions of tumor‐infitrating CD4+Foxp3+and Foxp3− cells from spleens, tumors, draining and nondraining lymph nodes, represented as CD62LhiCCR7+, CD62LloCCR7+ and CD62LloCCR7− (d and e) (n = 7). Expression of CD44 by CD62Lhi and CD62Llo cells (f).
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Show MeSH
Related in: MedlinePlus