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T cells contribute to tumor progression by favoring pro-tumoral properties of intra-tumoral myeloid cells in a mouse model for spontaneous melanoma.

Lengagne R, Pommier A, Caron J, Douguet L, Garcette M, Kato M, Avril MF, Abastado JP, Bercovici N, Lucas B, Prévost-Blondel A - PLoS ONE (2011)

Bottom Line: In the MT/ret model of spontaneous metastatic melanoma, myeloid cells are the most abundant tumor infiltrating hematopoietic population and their proportion is highest in the most aggressive cutaneous metastasis.Interestingly, T cells play a role in type 2 polarization of myeloid cells.Thus, our data support the existence of a vicious circle, in which T cells may favor cancer development by establishing an environment that is likely to skew myeloid cell immunity toward a tumor promoting response that, in turn, suppresses immune effector cell functions.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U1016, Institut Cochin, Paris, France.

ABSTRACT
Tumors affect myelopoeisis and induce the expansion of myeloid cells with immunosuppressive activity. In the MT/ret model of spontaneous metastatic melanoma, myeloid cells are the most abundant tumor infiltrating hematopoietic population and their proportion is highest in the most aggressive cutaneous metastasis. Our data suggest that the tumor microenvironment favors polarization of myeloid cells into type 2 cells characterized by F4/80 expression, a weak capacity to secrete IL-12 and a high production of arginase. Myeloid cells from tumor and spleen of MT/ret mice inhibit T cell proliferation and IFNγ secretion. Interestingly, T cells play a role in type 2 polarization of myeloid cells. Indeed, intra-tumoral myeloid cells from MT/ret mice lacking T cells are not only less suppressive towards T cells than corresponding cells from wild-type MT/ret mice, but they also inhibit more efficiently melanoma cell proliferation. Thus, our data support the existence of a vicious circle, in which T cells may favor cancer development by establishing an environment that is likely to skew myeloid cell immunity toward a tumor promoting response that, in turn, suppresses immune effector cell functions.

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T cells contribute to the immunosuppressive function of tumor infiltrating myeloid cells.(A) The graphs indicate the proportion of CD45+ cells from live cells and myeloid cells from CD45+ cells from tumors of RetCD3ε+ (n = 15) and RetCD3εKO (n = 16) age matched mice. (B) Cell suspensions from tumors derived from RetCD3ε+ and RetCD3εKO mice were stained for CD45, CD11b and IL4-Rα. Representative histograms are shown for IL4-Rα expression from CD45+CD11b+ cells. The histograms below summarize the MFI ratio of IL4-Rα specific staining on the isotype staining. Cell suspensions were also stained for CD45, CD11b and IL-12 after LPS and IFNγ stimulation. Representative IL-12/CD11b dot plots generated from gated CD45+ cells are shown. The histograms below summarize the proportion of IL-12 secreting cells from tumor infiltrating CD11b+ cells. Purified tumor infiltrating CD11b+ cells were activated with LPS and IFNγ for two days and assessed for NO production (C). (D) GP33-specific T cells (as in Figure 4.A) were stimulated 24 h with GP33 in presence of CD11b+ cells isolated from tumors of RetCD3ε+ (n = 5) or RetCD3εKO (n = 5) mice. T cell inhibition by myeloid cells is determined by comparing the frequency of IFNγ secreting cells in absence and in presence of CD11b+ cells.
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pone-0020235-g005: T cells contribute to the immunosuppressive function of tumor infiltrating myeloid cells.(A) The graphs indicate the proportion of CD45+ cells from live cells and myeloid cells from CD45+ cells from tumors of RetCD3ε+ (n = 15) and RetCD3εKO (n = 16) age matched mice. (B) Cell suspensions from tumors derived from RetCD3ε+ and RetCD3εKO mice were stained for CD45, CD11b and IL4-Rα. Representative histograms are shown for IL4-Rα expression from CD45+CD11b+ cells. The histograms below summarize the MFI ratio of IL4-Rα specific staining on the isotype staining. Cell suspensions were also stained for CD45, CD11b and IL-12 after LPS and IFNγ stimulation. Representative IL-12/CD11b dot plots generated from gated CD45+ cells are shown. The histograms below summarize the proportion of IL-12 secreting cells from tumor infiltrating CD11b+ cells. Purified tumor infiltrating CD11b+ cells were activated with LPS and IFNγ for two days and assessed for NO production (C). (D) GP33-specific T cells (as in Figure 4.A) were stimulated 24 h with GP33 in presence of CD11b+ cells isolated from tumors of RetCD3ε+ (n = 5) or RetCD3εKO (n = 5) mice. T cell inhibition by myeloid cells is determined by comparing the frequency of IFNγ secreting cells in absence and in presence of CD11b+ cells.

Mentions: To investigate the impact of T cells on the composition of hematopoietic cells within the tumor microenvironment and in particular on tumor infiltrating myeloid cells, we crossed MT/ret mice with CD3εKO mice. We found no change in the proportion of hematopoietic cells in mice competent (RetCD3ε+) and deficient (RetCD3εKO) for T cells. Tumor infiltrating myeloid cells represent 79% and 81% of CD45+ cells (Fig. 5A) and express a similar level of IL-4Rα (Fig. 5B) in the presence or in absence of T cells respectively. Interestingly, myeloid cells derived from RetCD3εKO mouse tumors exhibit a better capacity to secreteIL-12 (Fig. 5B) and NO (Fig. 5C) than the related cells from age-matched RetCD3ε+ mice. Moreover, they display a poor inhibitory effect on GP33-specific T cells stimulated with GP33 compared to myeloid cells from tumors of mice competent for T cells (Fig. 5D). By contrast, the proportion of IL-12 producing CD11b+ cells in spleen and their capacity to impair T cell functions are similar in both groups of animals lpar;not shown).


T cells contribute to tumor progression by favoring pro-tumoral properties of intra-tumoral myeloid cells in a mouse model for spontaneous melanoma.

Lengagne R, Pommier A, Caron J, Douguet L, Garcette M, Kato M, Avril MF, Abastado JP, Bercovici N, Lucas B, Prévost-Blondel A - PLoS ONE (2011)

T cells contribute to the immunosuppressive function of tumor infiltrating myeloid cells.(A) The graphs indicate the proportion of CD45+ cells from live cells and myeloid cells from CD45+ cells from tumors of RetCD3ε+ (n = 15) and RetCD3εKO (n = 16) age matched mice. (B) Cell suspensions from tumors derived from RetCD3ε+ and RetCD3εKO mice were stained for CD45, CD11b and IL4-Rα. Representative histograms are shown for IL4-Rα expression from CD45+CD11b+ cells. The histograms below summarize the MFI ratio of IL4-Rα specific staining on the isotype staining. Cell suspensions were also stained for CD45, CD11b and IL-12 after LPS and IFNγ stimulation. Representative IL-12/CD11b dot plots generated from gated CD45+ cells are shown. The histograms below summarize the proportion of IL-12 secreting cells from tumor infiltrating CD11b+ cells. Purified tumor infiltrating CD11b+ cells were activated with LPS and IFNγ for two days and assessed for NO production (C). (D) GP33-specific T cells (as in Figure 4.A) were stimulated 24 h with GP33 in presence of CD11b+ cells isolated from tumors of RetCD3ε+ (n = 5) or RetCD3εKO (n = 5) mice. T cell inhibition by myeloid cells is determined by comparing the frequency of IFNγ secreting cells in absence and in presence of CD11b+ cells.
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Related In: Results  -  Collection

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pone-0020235-g005: T cells contribute to the immunosuppressive function of tumor infiltrating myeloid cells.(A) The graphs indicate the proportion of CD45+ cells from live cells and myeloid cells from CD45+ cells from tumors of RetCD3ε+ (n = 15) and RetCD3εKO (n = 16) age matched mice. (B) Cell suspensions from tumors derived from RetCD3ε+ and RetCD3εKO mice were stained for CD45, CD11b and IL4-Rα. Representative histograms are shown for IL4-Rα expression from CD45+CD11b+ cells. The histograms below summarize the MFI ratio of IL4-Rα specific staining on the isotype staining. Cell suspensions were also stained for CD45, CD11b and IL-12 after LPS and IFNγ stimulation. Representative IL-12/CD11b dot plots generated from gated CD45+ cells are shown. The histograms below summarize the proportion of IL-12 secreting cells from tumor infiltrating CD11b+ cells. Purified tumor infiltrating CD11b+ cells were activated with LPS and IFNγ for two days and assessed for NO production (C). (D) GP33-specific T cells (as in Figure 4.A) were stimulated 24 h with GP33 in presence of CD11b+ cells isolated from tumors of RetCD3ε+ (n = 5) or RetCD3εKO (n = 5) mice. T cell inhibition by myeloid cells is determined by comparing the frequency of IFNγ secreting cells in absence and in presence of CD11b+ cells.
Mentions: To investigate the impact of T cells on the composition of hematopoietic cells within the tumor microenvironment and in particular on tumor infiltrating myeloid cells, we crossed MT/ret mice with CD3εKO mice. We found no change in the proportion of hematopoietic cells in mice competent (RetCD3ε+) and deficient (RetCD3εKO) for T cells. Tumor infiltrating myeloid cells represent 79% and 81% of CD45+ cells (Fig. 5A) and express a similar level of IL-4Rα (Fig. 5B) in the presence or in absence of T cells respectively. Interestingly, myeloid cells derived from RetCD3εKO mouse tumors exhibit a better capacity to secreteIL-12 (Fig. 5B) and NO (Fig. 5C) than the related cells from age-matched RetCD3ε+ mice. Moreover, they display a poor inhibitory effect on GP33-specific T cells stimulated with GP33 compared to myeloid cells from tumors of mice competent for T cells (Fig. 5D). By contrast, the proportion of IL-12 producing CD11b+ cells in spleen and their capacity to impair T cell functions are similar in both groups of animals lpar;not shown).

Bottom Line: In the MT/ret model of spontaneous metastatic melanoma, myeloid cells are the most abundant tumor infiltrating hematopoietic population and their proportion is highest in the most aggressive cutaneous metastasis.Interestingly, T cells play a role in type 2 polarization of myeloid cells.Thus, our data support the existence of a vicious circle, in which T cells may favor cancer development by establishing an environment that is likely to skew myeloid cell immunity toward a tumor promoting response that, in turn, suppresses immune effector cell functions.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U1016, Institut Cochin, Paris, France.

ABSTRACT
Tumors affect myelopoeisis and induce the expansion of myeloid cells with immunosuppressive activity. In the MT/ret model of spontaneous metastatic melanoma, myeloid cells are the most abundant tumor infiltrating hematopoietic population and their proportion is highest in the most aggressive cutaneous metastasis. Our data suggest that the tumor microenvironment favors polarization of myeloid cells into type 2 cells characterized by F4/80 expression, a weak capacity to secrete IL-12 and a high production of arginase. Myeloid cells from tumor and spleen of MT/ret mice inhibit T cell proliferation and IFNγ secretion. Interestingly, T cells play a role in type 2 polarization of myeloid cells. Indeed, intra-tumoral myeloid cells from MT/ret mice lacking T cells are not only less suppressive towards T cells than corresponding cells from wild-type MT/ret mice, but they also inhibit more efficiently melanoma cell proliferation. Thus, our data support the existence of a vicious circle, in which T cells may favor cancer development by establishing an environment that is likely to skew myeloid cell immunity toward a tumor promoting response that, in turn, suppresses immune effector cell functions.

Show MeSH
Related in: MedlinePlus