Progesterone-induced immunosuppression in breast cancer is mediated by the coordinated action of different immune escape mechanisms

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

Buenos Aires

Congreso; First French-Argentine Immunology Congress; 2010

Sociedad Argentina de Inmunología

Based on the anti-inflammatory and tolerogenic properties ofprogesterone and its ability to promote breast cancer progression,we sought to examine whether progesterone creates animmunosuppressive tumor microenvironment, either by controllinggalectin-glycan interactions, favoring the secretion ofinhibitory cytokines such as TGF-ß or inducing the differentiationof regulatory T cells (Tregs). The progesterone analoguemedroxiprogesterone acetate (MPA) markedly up-regulatedexpression of galectin-1 in two hormone-dependent humanbreast cancer cell lines and in a mouse mammary adenocarcinoma(C4HD) at both protein and mRNA levels (2-3 folds). Thiseffect was abrogated by pre-treatment with the antiprogestinRU486 indicating that the progesterone receptor was involved.In vitro MPA-treatment of mouse splenocytes induced a significantincrease in the frequency of Tregs (Ct 5±0.4%, MPA 10-7M 18±1.8%; p<0.01), skewed the balance toward a Th2-typecytokine profile (IFNγ/IL-10 Ct 25±2, MPA 3±0.4; p<0.01) andinduced a dose-dependent inhibition of T-cell proliferation(MPA 10-7M 50% inhibition). In vivo MPA-treatment of C4HDtumor-bearing mice increased the frequency of Tregs in spleen(Ct 11±0.4%, MPA 17±2%), tumor-draining lymph nodes (Ct10±0.4%, MPA 15±1.7%; p<0.05) and tumor microenvironment(Ct 12±4% MPA 25±6%; p<0.05). Augmented frequency of Tregcells induced by MPA was associated with increased synthesis ofTGF-ß1 and up-regulated expression of the SMAD4 transcriptionfactor (3-fold) in splenocytes suggesting a progesterone-regulatedaxis involving galectin-1, Treg cells and the TGF-ß pathway.Finally, progesterone favored the homing of Tregs to tumor sitesthrough induction of tumor-derived CCL22 (2-fold increase). Ourresults demonstrate that progesterone hierarchically fosters animmunosuppressive tumor microenvironment by co-ordinatelyregulating galectin-1 expression, stimulating the TGF-ß pathwayand augmenting the frequency of Treg cells.