CD11b+Ly6G+Ly6Cint myeloid-derived suppressor cells become expanded by medroxiprogesterone acetate in mammary tumor bearing hosts and suppress NK cell effector functions

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

Milán

Congreso; 15th International Congress of Immunology; 2013

International Union of Immunological Societies

The progesterone analogue medroxyprogesterone acetate (MPA) is being widely used in postmenopausal women, for the treatment of endometrial conditions, and as a contraceptive. However, hormone replacement therapy in postmenopausal women 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 mechanisms involving myeloid-derived suppressor cells (MDSCs; CD11b+Gr1+, composed by CD11b+Ly6G+Ly6Cint and CD11b+Ly6G-Ly6Chigh) and NK cells in mammary tumor-bearing mice. Using the highly metastatic 4T1 breast tumor (which does not express the classical progesterone 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 CD11b+Ly6G+Ly6Cint but not CD11b+Ly6G-Ly6Chigh cells. Also, MPA significantly increased the percentage of spleen and lung NK cells in tumor-bearing mice with similar lung infiltration of CD11b+Gr1+ cells as compared to untreated tumor-bearing mice. However, sorted CD11b+Gr1+ cells (comprising more than 90% of CD11b+Ly6G+Ly6Cint cells) from MPA-treated tumor bearing mice displayed a more pronounced suppressive activity on NK cell degranulation in response to YAC-1 cells and a stronger inhibition of IFN-g production of NK cells in response to cytokines than those CD11b+Gr1+ cells isolated from untreated tumor-bearing mice. Thus, in breast cancer-bearing hosts MPA promotes the accumulation of CD11b+Ly6G+Ly6Cint cells which display a suppressive activity on NK-cell effector functions, potentially contributing to tumor progression and metastasis.