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Spallanzani, R.G.; Dalotto-Moreno, T.; Raffo Iraolagoitia, X.L.; Ziblat, A.; Domaica, C.I.; Avila, D.E.; Rossi, L.E.; Fuertes, M.B.; Battistone, M.A.; Rabinovich, G.A.; Salatino, M.; Zwirner, N.W. "Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions" (2013) Cancer Immunology, Immunotherapy. 62(12):1781-1795
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Abstract:

The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b+Gr-1+, mostly CD11b +Ly6G+Ly6Cint and CD11b+Ly6G -Ly6Chigh cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b +Ly6G+Ly6Cint cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b+Ly6G+Ly6Cint cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b+Gr-1 + cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b+Gr-1 + cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b+Ly6G+Ly6Cint cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence. © 2013 Springer-Verlag Berlin Heidelberg.

Registro:

Documento: Artículo
Título:Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions
Autor:Spallanzani, R.G.; Dalotto-Moreno, T.; Raffo Iraolagoitia, X.L.; Ziblat, A.; Domaica, C.I.; Avila, D.E.; Rossi, L.E.; Fuertes, M.B.; Battistone, M.A.; Rabinovich, G.A.; Salatino, M.; Zwirner, N.W.
Filiación:Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad de Buenos Aires, Argentina
Laboratorio de Inmunopatología, IBYME, CONICET, Buenos Aires, Argentina
Cátedra de Inmunología, Facultad de Ciencias Exactas, Universidad Nacional de la Plata, La Plata, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
Laboratorio de Mecanismos Moleculares de la Fertilización, IBYME, CONICET, Buenos Aires, Argentina
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Buenos Aires, Argentina
Palabras clave:Breast cancer; Medroxyprogesterone acetate; Myeloid-derived suppressor cells; NK cells; CD11b antigen; dexamethasone; glucocorticoid receptor; medrosterona; medroxyprogesterone acetate; mifepristone; progesterone receptor; unclassified drug; animal cell; animal experiment; animal model; apoptosis; article; bone marrow; bone marrow cell; breast tumor; cell differentiation; cell expansion; cell function; cell line; cell motility; controlled study; cytotoxicity; degranulation; drug efficacy; drug exposure; effector cell; female; human; human cell; immunosurveillance; in vitro study; in vivo study; mouse; myeloid derived suppressor cell; natural killer cell; nonhuman; priority journal; protein expression; spleen; tumor cell; tumor growth; tumor volume; tumor xenograft; Animals; Antigens, CD11b; Antigens, Ly; Antineoplastic Agents, Hormonal; Blotting, Western; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Cytotoxicity, Immunologic; Female; Flow Cytometry; Fluorescent Antibody Technique; Humans; Killer Cells, Natural; Medroxyprogesterone Acetate; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid Cells; Receptors, Glucocorticoid; STAT3 Transcription Factor; Tumor Cells, Cultured
Año:2013
Volumen:62
Número:12
Página de inicio:1781
Página de fin:1795
DOI: http://dx.doi.org/10.1007/s00262-013-1483-x
Título revista:Cancer Immunology, Immunotherapy
Título revista abreviado:Cancer Immunol. Immunother.
ISSN:03407004
CODEN:CIIMD
CAS:dexamethasone, 50-02-2; medroxyprogesterone acetate, 71-58-9; mifepristone, 84371-65-3; Antigens, CD11b; Antigens, Ly; Antineoplastic Agents, Hormonal; Ly-6C antigen, mouse; Ly6G antigen, mouse; Medroxyprogesterone Acetate, C2QI4IOI2G; Receptors, Glucocorticoid; STAT3 Transcription Factor; Stat3 protein, mouse
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03407004_v62_n12_p1781_Spallanzani

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Citas:

---------- APA ----------
Spallanzani, R.G., Dalotto-Moreno, T., Raffo Iraolagoitia, X.L., Ziblat, A., Domaica, C.I., Avila, D.E., Rossi, L.E.,..., Zwirner, N.W. (2013) . Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions. Cancer Immunology, Immunotherapy, 62(12), 1781-1795.
http://dx.doi.org/10.1007/s00262-013-1483-x
---------- CHICAGO ----------
Spallanzani, R.G., Dalotto-Moreno, T., Raffo Iraolagoitia, X.L., Ziblat, A., Domaica, C.I., Avila, D.E., et al. "Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions" . Cancer Immunology, Immunotherapy 62, no. 12 (2013) : 1781-1795.
http://dx.doi.org/10.1007/s00262-013-1483-x
---------- MLA ----------
Spallanzani, R.G., Dalotto-Moreno, T., Raffo Iraolagoitia, X.L., Ziblat, A., Domaica, C.I., Avila, D.E., et al. "Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions" . Cancer Immunology, Immunotherapy, vol. 62, no. 12, 2013, pp. 1781-1795.
http://dx.doi.org/10.1007/s00262-013-1483-x
---------- VANCOUVER ----------
Spallanzani, R.G., Dalotto-Moreno, T., Raffo Iraolagoitia, X.L., Ziblat, A., Domaica, C.I., Avila, D.E., et al. Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions. Cancer Immunol. Immunother. 2013;62(12):1781-1795.
http://dx.doi.org/10.1007/s00262-013-1483-x