EXPANSION OF CD11b+Ly6G+Ly6Cint CELLS DRIVEN BY MEDROXIPROGESTERONE ACETATE IN BREAST CANCER-BEARING HOSTS RESTRAINS NK CELL EFFECTOR FUNCTIONS

SPALLANZANI GERMÁN R; DALOTTO MORENO TOMAS; RAFFO IRAOLAGOITIA XIMENA; ZIBLAT ANDREA; DOMAICA CAROLINA; AVILA DAMIAN; ROSSI LUCAS; FUERTES MERCEDES B; RABINOVICH GABRIEL A; SALATINO MARIANA; ZWIRNER NORBERTO W

CANCER IMMUNOLOGY IMMUNOTHERAPY

SPRINGER

Lugar: Berlin; Año: 2013 vol. 62 p. 1781 - 1795

0340-7004

The progesterone analogue medroxyprogesterone acetate (MPA) is widely used as hormone replacement therapy in postmenopausal women and as a 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 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 a depot of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice but with reduced degranulation ability. Simultaneously, MPA induced a preferential expansion of CD11b+Ly6G+Ly6Cint cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro experiments revealed that MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed them with the ability to promote a preferential differentiation of bone marrow cells into CD11b+Ly6G+Ly6Cint cells. Also, sorted CD11b+Gr-1+ cells from MPA-treated tumor-bearing mice (more than 90% of CD11b+Ly6G+Ly6Cint cells) exhibited higher suppressive activity on NK cell degranulation than CD11b+Gr-1+ cells from vehicle-treated tumor-bearing mice. Thus, MPA, most likely 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 affects the ability of the immune system to tackle tumor cells.