How does progesterone influence the host immune system during breast cancer?

SALATINO M; CROCI DO; DALOTTO T; SUNDBLAD V; ILARREGUI JM; TOSCANO MA; RABINOVICH GA

Viña del Mar, Chile.

Congreso; 9th Latin-American Congress of Immunology; 2009

Latin-American Association of Immunology

616 How does progesterone influence the host immune system during breast cancer? Mariana Salatino, Diego Omar Croci, Tom¨¢s Dalotto, Victoria Sundblad, Juan M. Ilarregui, Marta A. Toscano, Gabriel A. Rabinovich   Laboratorio de inmunopatolog¨ªa, IBYME - CONICET, Buenos Aires, Argentina.   Based on the tolerogenic properties of progesterone, and its promoting role in breast cancer, we investigated whether progesterone may create an immune privileged microenvironment in breast cancer, either by regulating galectin-1 expression or controlling regulatory T cell differentiation (Tregs= CD4+-CD25+-Foxp3+). The progesterone analogue medroxiprogesterone acetate (MPA) was capable of inducing galectin-1 expression in two hormone-dependent human breast cancer cell lines and in a murine mammary adenocarcinoma at both protein and mRNA levels (P<0.05). This effect was abrogated by pre-treatment with the antiprogestin RU486 indicating that the progesterone receptor was involved in this effect. Interestingly, in vitro MPA-treatment of mouse splenocytes or human PBMC induced a significant increase in the frequency of Tregs and skewed the balance toward a Th2-type cytokine profile (P< 0.01). In vivo MPA-treatment increased the frequency of Tregs in tumor-draining lymph nodes and within the tumor microenvironment (P<0.05). Progesterone-induced increase of Tregs was associated with an effect of MPA on SMAD4 expression, a signalling pathway commonly associated to TGF-¦Â signaling, On the other hand, progesterone favored the homing of Tregs to the tumor milieu through the induction of tumor-derived CCL22. Our results demonstrate that progesterone fosters an immunosuppressive or tolerogenic tumor stroma by regulating galectin-1 expression and augmenting the frequency of Tregs in breast cancer.