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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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Accumulation of CD11b+Gr1high myeloid cells in spleen of tumor bearing MT/ret mice.(A) Comparison of the proportion of hematopoietic cells in spleen of MT/ret and ctrl mice. Myeloid cells are CD11b+ cells. αβT cells are defined as CD4+ αβTCRhigh cells and CD8+ αβTCRhigh cells. γδT cells are defined as CD8- γδTCRhigh cells. B cells are defined as CD19+CD8- cells and NK cells are NK1.1+CD4-CD8- cells. The pie diagram summarizes data from spleens of MT/ret (n = 29) and Ctrl (n = 13) age matched mice. (B) Single cell suspensions derived from spleens of MT/ret or Ctrl mice were stained for CD45, CD11b and Gr1. Representative CD11b/Gr1 dot plots were generated from gated CD45+ cells. (C) The histograms correspond to the absolute numbers of both CD11b+Gr1high cell subsets in ctrl spleens (n = 13) and in spleens of MT/ret mice displaying either primary tumors (n = 8), facial (face, n = 13) or dorsal cutaneous metastasis (back, n = 12). (D) Myeloid cells from MT/ret spleen inhibit the spontaneous response specific for melanoma. The number of IFNγ-secreting cells was assessed by an ELISPOT assay using splenocytes from MT/ret mice as effectors and Melan-ret cells as targets. Ex vivo splenocytes were used either in total or after depletion of CD11b+ cells. The significance was assessed using unpaired t test.
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pone-0020235-g001: Accumulation of CD11b+Gr1high myeloid cells in spleen of tumor bearing MT/ret mice.(A) Comparison of the proportion of hematopoietic cells in spleen of MT/ret and ctrl mice. Myeloid cells are CD11b+ cells. αβT cells are defined as CD4+ αβTCRhigh cells and CD8+ αβTCRhigh cells. γδT cells are defined as CD8- γδTCRhigh cells. B cells are defined as CD19+CD8- cells and NK cells are NK1.1+CD4-CD8- cells. The pie diagram summarizes data from spleens of MT/ret (n = 29) and Ctrl (n = 13) age matched mice. (B) Single cell suspensions derived from spleens of MT/ret or Ctrl mice were stained for CD45, CD11b and Gr1. Representative CD11b/Gr1 dot plots were generated from gated CD45+ cells. (C) The histograms correspond to the absolute numbers of both CD11b+Gr1high cell subsets in ctrl spleens (n = 13) and in spleens of MT/ret mice displaying either primary tumors (n = 8), facial (face, n = 13) or dorsal cutaneous metastasis (back, n = 12). (D) Myeloid cells from MT/ret spleen inhibit the spontaneous response specific for melanoma. The number of IFNγ-secreting cells was assessed by an ELISPOT assay using splenocytes from MT/ret mice as effectors and Melan-ret cells as targets. Ex vivo splenocytes were used either in total or after depletion of CD11b+ cells. The significance was assessed using unpaired t test.

Mentions: The MT/ret model allowed the monitoring of immune cells within the spleen and the tumor microenvironment during the course of spontaneous tumor progression. Exophthalmus corresponds to the first clinical sign of uveal primary melanoma development. Within 3 months after birth, 50% of mice display cutaneous metastasis that develop first on the face, then in the posterior part of the body [34]. The proportions of hematopoietic populations within spleens derived from age matched MT/ret and ctrl mice were not statistically different (Fig. 1A). However, CD11b+ cells consist of two main populations according to Gr1 expression level, Gr1low (monocytic) and Gr1high (granulocytic), and the proportions of CD11b+ subsets in MT/ret mice differ from those in ctrl mice. More precisely, CD11b+Gr1high cells accumulate in spleen of mice displaying dorsal metastasis corresponding to a late melanoma stage (Fig. 1B and C). In addition, we have previously shown that MT/ret mice develop anti-tumor immune response spontaneously during disease progression [34]. To evaluate if this anti-tumor immune response is negatively influenced by myeloid cells in the spleen, either total splenocytes or CD11b+ cell-depleted splenocytes were stimulated with Melan-ret melanoma cells. The removal of CD11b+ cells raises the number of splenocytes responding to melanoma cells (Fig. 1D). Together our data indicate that, as shown in models of tumor transplantation, myeloid cells accumulate within spleen of MT/ret mice and prevent optimal anti-tumor T cell response.


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)

Accumulation of CD11b+Gr1high myeloid cells in spleen of tumor bearing MT/ret mice.(A) Comparison of the proportion of hematopoietic cells in spleen of MT/ret and ctrl mice. Myeloid cells are CD11b+ cells. αβT cells are defined as CD4+ αβTCRhigh cells and CD8+ αβTCRhigh cells. γδT cells are defined as CD8- γδTCRhigh cells. B cells are defined as CD19+CD8- cells and NK cells are NK1.1+CD4-CD8- cells. The pie diagram summarizes data from spleens of MT/ret (n = 29) and Ctrl (n = 13) age matched mice. (B) Single cell suspensions derived from spleens of MT/ret or Ctrl mice were stained for CD45, CD11b and Gr1. Representative CD11b/Gr1 dot plots were generated from gated CD45+ cells. (C) The histograms correspond to the absolute numbers of both CD11b+Gr1high cell subsets in ctrl spleens (n = 13) and in spleens of MT/ret mice displaying either primary tumors (n = 8), facial (face, n = 13) or dorsal cutaneous metastasis (back, n = 12). (D) Myeloid cells from MT/ret spleen inhibit the spontaneous response specific for melanoma. The number of IFNγ-secreting cells was assessed by an ELISPOT assay using splenocytes from MT/ret mice as effectors and Melan-ret cells as targets. Ex vivo splenocytes were used either in total or after depletion of CD11b+ cells. The significance was assessed using unpaired t test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3102108&req=5

pone-0020235-g001: Accumulation of CD11b+Gr1high myeloid cells in spleen of tumor bearing MT/ret mice.(A) Comparison of the proportion of hematopoietic cells in spleen of MT/ret and ctrl mice. Myeloid cells are CD11b+ cells. αβT cells are defined as CD4+ αβTCRhigh cells and CD8+ αβTCRhigh cells. γδT cells are defined as CD8- γδTCRhigh cells. B cells are defined as CD19+CD8- cells and NK cells are NK1.1+CD4-CD8- cells. The pie diagram summarizes data from spleens of MT/ret (n = 29) and Ctrl (n = 13) age matched mice. (B) Single cell suspensions derived from spleens of MT/ret or Ctrl mice were stained for CD45, CD11b and Gr1. Representative CD11b/Gr1 dot plots were generated from gated CD45+ cells. (C) The histograms correspond to the absolute numbers of both CD11b+Gr1high cell subsets in ctrl spleens (n = 13) and in spleens of MT/ret mice displaying either primary tumors (n = 8), facial (face, n = 13) or dorsal cutaneous metastasis (back, n = 12). (D) Myeloid cells from MT/ret spleen inhibit the spontaneous response specific for melanoma. The number of IFNγ-secreting cells was assessed by an ELISPOT assay using splenocytes from MT/ret mice as effectors and Melan-ret cells as targets. Ex vivo splenocytes were used either in total or after depletion of CD11b+ cells. The significance was assessed using unpaired t test.
Mentions: The MT/ret model allowed the monitoring of immune cells within the spleen and the tumor microenvironment during the course of spontaneous tumor progression. Exophthalmus corresponds to the first clinical sign of uveal primary melanoma development. Within 3 months after birth, 50% of mice display cutaneous metastasis that develop first on the face, then in the posterior part of the body [34]. The proportions of hematopoietic populations within spleens derived from age matched MT/ret and ctrl mice were not statistically different (Fig. 1A). However, CD11b+ cells consist of two main populations according to Gr1 expression level, Gr1low (monocytic) and Gr1high (granulocytic), and the proportions of CD11b+ subsets in MT/ret mice differ from those in ctrl mice. More precisely, CD11b+Gr1high cells accumulate in spleen of mice displaying dorsal metastasis corresponding to a late melanoma stage (Fig. 1B and C). In addition, we have previously shown that MT/ret mice develop anti-tumor immune response spontaneously during disease progression [34]. To evaluate if this anti-tumor immune response is negatively influenced by myeloid cells in the spleen, either total splenocytes or CD11b+ cell-depleted splenocytes were stimulated with Melan-ret melanoma cells. The removal of CD11b+ cells raises the number of splenocytes responding to melanoma cells (Fig. 1D). Together our data indicate that, as shown in models of tumor transplantation, myeloid cells accumulate within spleen of MT/ret mice and prevent optimal anti-tumor T cell response.

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