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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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Characterization of hematopoietic cells within the tumor microenvironment of MT/ret mice.(A) Dot plots from a cell suspension of one representative cutaneous metastasis. Myeloid and lymphoid stainings were performed as defined in Fig 1A. (B) The pie diagram summarizes the proportion of hematopoietic cells from 47 cutaneous metastasis. (C) Variability of the proportion of tumor infiltrating CD11b+ cells from cutaneous metastasis. The frequencies of CD11b+ cells gated from CD45+ cells were determined. The graph shows the data for four 3 month old mice. (D) Correlation between the tumor aggressiveness and the increase of tumor infiltrating CD11b+ cells. The tumor aggressiveness corresponds to the ratio between the absolute numbers of tumor associated cells and the number of days since appearance of each nodule. Statistical differences were assessed using ANOVA test.
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pone-0020235-g002: Characterization of hematopoietic cells within the tumor microenvironment of MT/ret mice.(A) Dot plots from a cell suspension of one representative cutaneous metastasis. Myeloid and lymphoid stainings were performed as defined in Fig 1A. (B) The pie diagram summarizes the proportion of hematopoietic cells from 47 cutaneous metastasis. (C) Variability of the proportion of tumor infiltrating CD11b+ cells from cutaneous metastasis. The frequencies of CD11b+ cells gated from CD45+ cells were determined. The graph shows the data for four 3 month old mice. (D) Correlation between the tumor aggressiveness and the increase of tumor infiltrating CD11b+ cells. The tumor aggressiveness corresponds to the ratio between the absolute numbers of tumor associated cells and the number of days since appearance of each nodule. Statistical differences were assessed using ANOVA test.

Mentions: To extent these data to the monitoring of the tumor microenvironment, we first compared the proportion of hematopoietic cells that infiltrate cutaneous metastasis derived from 3 to 6 month old MT/ret mice (Fig. 2A, 2B). CD45+ cells represent 2.3% of total cells. αβT and B cells represent on an 6+/−0.5% and 6.7+/−0.8% of hematopoietic cells respectively. The percentages of γδT and NK cells are pretty low. More interestingly, the percentage of CD11b+ cells ranges from 11.6 to 92.4% with an average 76.1% of CD45+ cells and they are almost exclusively Gr1low. In a given mouse, the proportion of CD11b+ cells could be variable from tumor to tumor as shown in Fig. 2C for 4 mice. In order to evaluate the association of tumor infiltrating myeloid cells with tumor progression for one given nodule, we defined a “tumor aggressiveness score” corresponding to the ratio between the absolute number of cells in the tumor and the number of days since its appearance. The most aggressive tumors (>2.105 cells/day) displayed a high proportion of CD11b+ cells, whereas the less aggressive ones (<2.104 cells/day) are significantly less infiltrated by myeloid cells (Fig. 2D). Tumors with intermediate aggressiveness already displayed an increased proportion of CD11b+ cells.


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)

Characterization of hematopoietic cells within the tumor microenvironment of MT/ret mice.(A) Dot plots from a cell suspension of one representative cutaneous metastasis. Myeloid and lymphoid stainings were performed as defined in Fig 1A. (B) The pie diagram summarizes the proportion of hematopoietic cells from 47 cutaneous metastasis. (C) Variability of the proportion of tumor infiltrating CD11b+ cells from cutaneous metastasis. The frequencies of CD11b+ cells gated from CD45+ cells were determined. The graph shows the data for four 3 month old mice. (D) Correlation between the tumor aggressiveness and the increase of tumor infiltrating CD11b+ cells. The tumor aggressiveness corresponds to the ratio between the absolute numbers of tumor associated cells and the number of days since appearance of each nodule. Statistical differences were assessed using ANOVA test.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3102108&req=5

pone-0020235-g002: Characterization of hematopoietic cells within the tumor microenvironment of MT/ret mice.(A) Dot plots from a cell suspension of one representative cutaneous metastasis. Myeloid and lymphoid stainings were performed as defined in Fig 1A. (B) The pie diagram summarizes the proportion of hematopoietic cells from 47 cutaneous metastasis. (C) Variability of the proportion of tumor infiltrating CD11b+ cells from cutaneous metastasis. The frequencies of CD11b+ cells gated from CD45+ cells were determined. The graph shows the data for four 3 month old mice. (D) Correlation between the tumor aggressiveness and the increase of tumor infiltrating CD11b+ cells. The tumor aggressiveness corresponds to the ratio between the absolute numbers of tumor associated cells and the number of days since appearance of each nodule. Statistical differences were assessed using ANOVA test.
Mentions: To extent these data to the monitoring of the tumor microenvironment, we first compared the proportion of hematopoietic cells that infiltrate cutaneous metastasis derived from 3 to 6 month old MT/ret mice (Fig. 2A, 2B). CD45+ cells represent 2.3% of total cells. αβT and B cells represent on an 6+/−0.5% and 6.7+/−0.8% of hematopoietic cells respectively. The percentages of γδT and NK cells are pretty low. More interestingly, the percentage of CD11b+ cells ranges from 11.6 to 92.4% with an average 76.1% of CD45+ cells and they are almost exclusively Gr1low. In a given mouse, the proportion of CD11b+ cells could be variable from tumor to tumor as shown in Fig. 2C for 4 mice. In order to evaluate the association of tumor infiltrating myeloid cells with tumor progression for one given nodule, we defined a “tumor aggressiveness score” corresponding to the ratio between the absolute number of cells in the tumor and the number of days since its appearance. The most aggressive tumors (>2.105 cells/day) displayed a high proportion of CD11b+ cells, whereas the less aggressive ones (<2.104 cells/day) are significantly less infiltrated by myeloid cells (Fig. 2D). Tumors with intermediate aggressiveness already displayed an increased proportion of CD11b+ cells.

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