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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 myeloid cells from MT/ret mice.(A) QPCR. CD11b+ cells were isolated from tumors and spleens of tumor bearing MT/ret mice. The transcripts levels of a panel of genes were analyzed by RT-PCR. Mean values+/− SEM of relative expression are shown for indicated genes. (B) Phenotype and function of CD11b+ cells. Cell suspensions from tumors and spleens of MT/ret mice were stained for CD45, CD11b and IL4-Rα, F4/80 and IL12 and their isotype controls (grey histogram). Representative stainings for spleen (single line) and tumor (bold line) are shown. IL-12/CD11b+ dot plots generated from gated CD45+ cells are obtained after stimulation with IFNγ and LPS. Representative histograms of more than 3 experiments and performed on more than 10 samples are shown. Results are expressed as the percentage of IL-12+ cells from CD45+CD11b+Gr1+ cells taking account the two Gr1 subsets within spleens. Statistical differences were assessed using unpaired t test.
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pone-0020235-g003: Characterization of myeloid cells from MT/ret mice.(A) QPCR. CD11b+ cells were isolated from tumors and spleens of tumor bearing MT/ret mice. The transcripts levels of a panel of genes were analyzed by RT-PCR. Mean values+/− SEM of relative expression are shown for indicated genes. (B) Phenotype and function of CD11b+ cells. Cell suspensions from tumors and spleens of MT/ret mice were stained for CD45, CD11b and IL4-Rα, F4/80 and IL12 and their isotype controls (grey histogram). Representative stainings for spleen (single line) and tumor (bold line) are shown. IL-12/CD11b+ dot plots generated from gated CD45+ cells are obtained after stimulation with IFNγ and LPS. Representative histograms of more than 3 experiments and performed on more than 10 samples are shown. Results are expressed as the percentage of IL-12+ cells from CD45+CD11b+Gr1+ cells taking account the two Gr1 subsets within spleens. Statistical differences were assessed using unpaired t test.

Mentions: To further compare myeloid cells that accumulate during tumor progression, quantitative PCR were carried out on CD11b+ purified cells from spleen and tumor samples using a set of type 2 myeloid-associated marker genes. QPCR analysis revealed that il10, arginase I, mgl1 fizz1 and the inflammatory chemokine ccl2 mRNA levels were all significantly higher in tumor derived CD11b+ cells (Fig. 3A). In addition, these cells were strongly positive for F4/80 mRNA compared to related cells in spleen. Flow cytometric analysis further showed that tumor infiltrating myeloid cells express F4/80 at the protein level, revealing a significant upregulation of this macrophage marker in the tumor microenvironment (Fig. 3B). In addition, tumor infiltrating myeloid cells express IL-4Rα (Fig. 3B). Contrasting with transplanted tumor models [12], IL-4Rα expression in spleen of tumor-bearing MT/ret mice is low (Fig. 3B) and similar to the level observed in splenocytes from control mice (data not shown). A relatively low proportion of tumor infiltrating myeloid cells secrete IL-12 upon a short IFNγ/LPS stimulation (2.7+/−0.8; Fig. 3B), a proportion quite similar to that of related splenic myeloid cells. Overall, tumor infiltrating myeloid cells are enriched in F4/80+, IL-4Rα+ cells and only a minority of them have the capacity to produce IL-12.


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 myeloid cells from MT/ret mice.(A) QPCR. CD11b+ cells were isolated from tumors and spleens of tumor bearing MT/ret mice. The transcripts levels of a panel of genes were analyzed by RT-PCR. Mean values+/− SEM of relative expression are shown for indicated genes. (B) Phenotype and function of CD11b+ cells. Cell suspensions from tumors and spleens of MT/ret mice were stained for CD45, CD11b and IL4-Rα, F4/80 and IL12 and their isotype controls (grey histogram). Representative stainings for spleen (single line) and tumor (bold line) are shown. IL-12/CD11b+ dot plots generated from gated CD45+ cells are obtained after stimulation with IFNγ and LPS. Representative histograms of more than 3 experiments and performed on more than 10 samples are shown. Results are expressed as the percentage of IL-12+ cells from CD45+CD11b+Gr1+ cells taking account the two Gr1 subsets within spleens. Statistical differences were 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-g003: Characterization of myeloid cells from MT/ret mice.(A) QPCR. CD11b+ cells were isolated from tumors and spleens of tumor bearing MT/ret mice. The transcripts levels of a panel of genes were analyzed by RT-PCR. Mean values+/− SEM of relative expression are shown for indicated genes. (B) Phenotype and function of CD11b+ cells. Cell suspensions from tumors and spleens of MT/ret mice were stained for CD45, CD11b and IL4-Rα, F4/80 and IL12 and their isotype controls (grey histogram). Representative stainings for spleen (single line) and tumor (bold line) are shown. IL-12/CD11b+ dot plots generated from gated CD45+ cells are obtained after stimulation with IFNγ and LPS. Representative histograms of more than 3 experiments and performed on more than 10 samples are shown. Results are expressed as the percentage of IL-12+ cells from CD45+CD11b+Gr1+ cells taking account the two Gr1 subsets within spleens. Statistical differences were assessed using unpaired t test.
Mentions: To further compare myeloid cells that accumulate during tumor progression, quantitative PCR were carried out on CD11b+ purified cells from spleen and tumor samples using a set of type 2 myeloid-associated marker genes. QPCR analysis revealed that il10, arginase I, mgl1 fizz1 and the inflammatory chemokine ccl2 mRNA levels were all significantly higher in tumor derived CD11b+ cells (Fig. 3A). In addition, these cells were strongly positive for F4/80 mRNA compared to related cells in spleen. Flow cytometric analysis further showed that tumor infiltrating myeloid cells express F4/80 at the protein level, revealing a significant upregulation of this macrophage marker in the tumor microenvironment (Fig. 3B). In addition, tumor infiltrating myeloid cells express IL-4Rα (Fig. 3B). Contrasting with transplanted tumor models [12], IL-4Rα expression in spleen of tumor-bearing MT/ret mice is low (Fig. 3B) and similar to the level observed in splenocytes from control mice (data not shown). A relatively low proportion of tumor infiltrating myeloid cells secrete IL-12 upon a short IFNγ/LPS stimulation (2.7+/−0.8; Fig. 3B), a proportion quite similar to that of related splenic myeloid cells. Overall, tumor infiltrating myeloid cells are enriched in F4/80+, IL-4Rα+ cells and only a minority of them have the capacity to produce IL-12.

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