Progesterone-induced immunosuppression in breast cancer promotes lung metastasis

TOMÁS DALOTTO; DIEGO O. CROCI; VICTORIA SUNDBLAD; SEBASTIAN DERGAN-DYLON; IVAN D. MASCANFRONI; JUAN P. CERLIANI; GABRIEL A. RABINOVICH; MARIANA SALATINO

Buenos Aires

Congreso; 1° Congreso Franco-Argentino de Inmunología - LVIII Reunión Anual de la Sociedad Argentina de Inmunología; 2010

Progesterone is a sexual steroid with immunosuppressive and tolerogenic properties that plays a crucial role in breast cancer progression. Here we investigated whether progesterone promotes tumor progression and metastasis in a hormone-independent breast tumor model by promoting an immunosuppressive tumor microenvironment. We used the invasive 4T1 mammary carcinoma that metastasizes to lymph nodes and lung. We observed that 4T1 cell line expressed high levels of galectin-1 (Gal1) as compared with normal gland tissue and other breast tumor cell lines. Progesterone (medroxiprogesterone acetate=MPA) treatment of 4T1 tumor-bearing mice increased Gal1 expression in the tumor stroma (2-fold) indicating that progesterone induced the recruitment of a Gal1+ population within the tumor. As regulatory T cells (Tregs) express high levels of Gal1, we then studied whether progesterone facilitates Treg cell differentiation and their recruitment to tumor sites. Interestingly, MPA augmented Treg cell frequency in the spleen both in tumor-free and in tumor-bearing mice (Ct 12% MPA14.5% 4T1 12% 4T1+MPA 15%; p<0.05). This increase in Treg cell frequency was accompanied with an induction in Treg cell homing to tumor sites (Ct 40±5% MPA60±8%; p<0.05). Increased Treg cell infiltration induced by MPA was dependent on the expression of tumor-derived Gal1, as 4T1 Gal1 knockdown tumors recruit significantly lower amounts of Treg cells to lymph nodes and tumor sites as compared to Gal1-expressing 4T1 tumors (4T1Scr 60±8% vs 4T1RNAsh3.7 38±2% p<0.05). Finally, in vivo treatment of mice with MPA induced lung tumor micrometastasis following inoculation of Gal1-expressing but not Gal1 knockdown 4T1 tumors (4T1Scr 325±20 4T1RNAsh3.7 60±8; p<0.01). These results indicate that progesterone fosters an immunosuppressive tumor microenvironment that facilitates lung metastasis through a pathway involving galectin-1-induced immunoregulation and recruitment of Treg cells to site of tumor growth.