Granulocytic myeloid-derived suppressor cells become expanded by medroxyprogesterone acetate in mammary tumor bearing hosts and suppress NK cell effector functions

SPALLANZANI, RAÚL GERMÁN; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; ZIBLAT, ANDREA; DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; DALOTTO-MORENO, TOMÁS; RABINOVICH, GABRIEL ADRIÁN; SALATINO, MARIANA; ZWIRNER, NORBERTO WALTER

Los Cocos

Congreso; 61a Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Sociedad Argentina de Inmunología

Medroxyprogesterone acetate (MPA) is a progesterone (Pg) analogue with glucocorticoid activity widely used as a contraceptive and in postmenopausal women as hormone replacement therapy. As chronic treatment with MPA has been associated with increased incidence of breast cancer through ill-defined mechanisms, in this work we explored whether prolonged exposure to MPA restrains immunosurveillance to tumors through myeloid-derived suppressor cells (MDSCs; CD11b+Gr1+), composed by Granulocytic-MDSCs (G-MDSCs; CD11b+Ly6G+Ly6Cint) and Monocytic-MDSCs (M-MDSCs; CD11b+Ly6G-Ly6Chigh), and NK cells in mammary tumor-bearing mice. Using the highly metastatic 4T1 breast tumor which expresses the glucocorticoid receptor (GR) but not the classical Pg receptor, we observed that MPA did not affect primary tumor growth but promoted lung metastasis burden. This effect was accompanied by a preferential expansion of spleen and bone marrow (BM) G-MDSCs (p<0,01) but not M-MDSCs. Sorted MDSCs (>90% of G-MDSCs) from MPA-treated tumor bearing mice displayed a more pronounced suppressive activity on NK cell degranulation than MDSCs from untreated tumor-bearing mice (p<0,05). Also, tumor-bearing mice exposed to MPA exhibited decreased in vivo NK cell-mediated cytotoxicity compared to untreated tumor-bearing mice. Conditioned media (CM) from 4T1 cells cultured with MPA induced a heightened expansion of BM MDSCs that displayed a stronger inhibition of NK cell degranulation than CM from 4T1 cells cultured alone. As MPA induced nuclear mobilization of GR and the GR specific inhibitor 21-Hydroxy-6,19-epoxyprogesterone reversed MPA-mediated BM-MDSCs expansion in vitro, we conclude that MPA signals via GR to induce the observed phenomena. Thus, in breast cancer-bearing hosts MPA endows tumor cells with the ability to promote a heightened accumulation of G-MDSCs that display a stronger suppressive activity on NK cell cytotoxicity, potentially contributing to tumor progression and metastasis.