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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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CD11b+ cells from MT/ret mice suppress T cell functions.(A) GP33-specific T cells from GP33-immunized mice were stimulated 24 h with GP33 in presence of CD11b+ cells isolated either from tumors or spleens of MT/ret mice or ctrl spleens. The frequency of IFNγ secreting T cells was determined by an ELISPOT assay. The percentage of inhibition indicated on the graph corresponds to the ratio between the number of spots in presence and in absence of CD11b+ (upper histogram). GP33-specific T cells were also stimulated with GP33 together with supernatants of CD11b+ cells isolated from tumors or spleens of MT/ret or non transgenic mice and tested as above (lower histogram). (B) Purified OT-1 CD8+ T cells labeled with CFSE were cultured in presence of CD11b+ cells isolated from spleens or tumor nodules from MT/ret mice or from ctrl spleen, and stimulated in presence or not of Ova257. Three days later, proliferation was determined. CFSE fluorescences are shown after culture with (bold lines) or without Ova257 (thin lines).
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pone-0020235-g004: CD11b+ cells from MT/ret mice suppress T cell functions.(A) GP33-specific T cells from GP33-immunized mice were stimulated 24 h with GP33 in presence of CD11b+ cells isolated either from tumors or spleens of MT/ret mice or ctrl spleens. The frequency of IFNγ secreting T cells was determined by an ELISPOT assay. The percentage of inhibition indicated on the graph corresponds to the ratio between the number of spots in presence and in absence of CD11b+ (upper histogram). GP33-specific T cells were also stimulated with GP33 together with supernatants of CD11b+ cells isolated from tumors or spleens of MT/ret or non transgenic mice and tested as above (lower histogram). (B) Purified OT-1 CD8+ T cells labeled with CFSE were cultured in presence of CD11b+ cells isolated from spleens or tumor nodules from MT/ret mice or from ctrl spleen, and stimulated in presence or not of Ova257. Three days later, proliferation was determined. CFSE fluorescences are shown after culture with (bold lines) or without Ova257 (thin lines).

Mentions: To compare the impact of myeloid cells from tumor bearing MT/ret mice on T cell functions, we first stimulated T cells from GP33 immunized mice with GP33 in the presence of CD11b+ cells. CD11b+ cells isolated from tumors or spleens of MT/ret mice inhibit IFNγ secretion (78% and 61% inhibition respectively) (Fig. 4A, upper histogram). Supernatants from tumor- or spleen-derived CD11b+ cells of MT/ret mice also reduced the proportions of IFNγ secreting T cells (49% and 40% inhibition respectively), while supernatant from control mice had no effect (Fig. 4A, lower histogram). In addition, we cultured CD11b+ cells with CD8+ T cells specific for Ova257 peptide from OT-1 mice. In the presence of Ova257 and control CD11b+ cells, a majority of OT-1 cells undergoes three to four cycles, whereas CD11b+ cells derived from tumors or spleens of MT/ret mice reduced Ova257 specific T cell division (Fig. 4B). Together our data indicate that despite their phenotypic differences described above, both splenic and tumor derived myeloid populations inhibit CD8+ T cell proliferation and IFNγ secretion.


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)

CD11b+ cells from MT/ret mice suppress T cell functions.(A) GP33-specific T cells from GP33-immunized mice were stimulated 24 h with GP33 in presence of CD11b+ cells isolated either from tumors or spleens of MT/ret mice or ctrl spleens. The frequency of IFNγ secreting T cells was determined by an ELISPOT assay. The percentage of inhibition indicated on the graph corresponds to the ratio between the number of spots in presence and in absence of CD11b+ (upper histogram). GP33-specific T cells were also stimulated with GP33 together with supernatants of CD11b+ cells isolated from tumors or spleens of MT/ret or non transgenic mice and tested as above (lower histogram). (B) Purified OT-1 CD8+ T cells labeled with CFSE were cultured in presence of CD11b+ cells isolated from spleens or tumor nodules from MT/ret mice or from ctrl spleen, and stimulated in presence or not of Ova257. Three days later, proliferation was determined. CFSE fluorescences are shown after culture with (bold lines) or without Ova257 (thin lines).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102108&req=5

pone-0020235-g004: CD11b+ cells from MT/ret mice suppress T cell functions.(A) GP33-specific T cells from GP33-immunized mice were stimulated 24 h with GP33 in presence of CD11b+ cells isolated either from tumors or spleens of MT/ret mice or ctrl spleens. The frequency of IFNγ secreting T cells was determined by an ELISPOT assay. The percentage of inhibition indicated on the graph corresponds to the ratio between the number of spots in presence and in absence of CD11b+ (upper histogram). GP33-specific T cells were also stimulated with GP33 together with supernatants of CD11b+ cells isolated from tumors or spleens of MT/ret or non transgenic mice and tested as above (lower histogram). (B) Purified OT-1 CD8+ T cells labeled with CFSE were cultured in presence of CD11b+ cells isolated from spleens or tumor nodules from MT/ret mice or from ctrl spleen, and stimulated in presence or not of Ova257. Three days later, proliferation was determined. CFSE fluorescences are shown after culture with (bold lines) or without Ova257 (thin lines).
Mentions: To compare the impact of myeloid cells from tumor bearing MT/ret mice on T cell functions, we first stimulated T cells from GP33 immunized mice with GP33 in the presence of CD11b+ cells. CD11b+ cells isolated from tumors or spleens of MT/ret mice inhibit IFNγ secretion (78% and 61% inhibition respectively) (Fig. 4A, upper histogram). Supernatants from tumor- or spleen-derived CD11b+ cells of MT/ret mice also reduced the proportions of IFNγ secreting T cells (49% and 40% inhibition respectively), while supernatant from control mice had no effect (Fig. 4A, lower histogram). In addition, we cultured CD11b+ cells with CD8+ T cells specific for Ova257 peptide from OT-1 mice. In the presence of Ova257 and control CD11b+ cells, a majority of OT-1 cells undergoes three to four cycles, whereas CD11b+ cells derived from tumors or spleens of MT/ret mice reduced Ova257 specific T cell division (Fig. 4B). Together our data indicate that despite their phenotypic differences described above, both splenic and tumor derived myeloid populations inhibit CD8+ T cell proliferation and IFNγ secretion.

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