(537) PROGESTIN-DRIVEN REGULATORY T CELLS

DALOTTO-MORENO T; MENDEZ-HUERGO S; MOSES F; RABINOVICH GA; SALATINO M

Congreso; Reunión Anual de la Sociedad Argentina de Inmunología; 2014

The immune system plays key roles in the elimination of mosttumors. Progesterone (Pg) can shape the immune responsefavoring a tolerogenic rather than a pro-inflammatory adaptiveresponse. As hormone supplement therapies have been associatedwith increased frequency of malignant breast neoplasias,we investigated, using the triple negative 4T1 breast tumor, howprogestins can regulate key immune cell populations in the tumormicroenvironment and how progestin-induced immunosuppressioninfluences to tumor progression. Balb/c mice treated with Pg or itssynthetic analog, medroxyprogesterone acetate (MPA), showed anincreased frequency of Foxp3+ regulatory T cells (Tregs) in draininglymph nodes and displayed an impaired antitumor responseevidenced by a decreased production of IL-17 and IFN-ã by CD4+T cells (p<0.01). Progestin-treated tumor-bearing mice showed ahigher frequency of both Tregs and PD1+TIM3+ exhausted tumorassociatedT cells (p<0.05). Although primary tumor growth wasnot altered, the number of lung metastases considerably increasedin mice treated with progestins (p<0.01). Both Pg and MPA favoredstable differentiation and expansion of Tregs, leading to augmentedimmunosuppressive activity (p<0.01). In the presence ofprogestins, in vitro differentiated Tregs showed higher expressionof RANKL, a protein involved in malignant transformation. Whenco-cultured, ex vivo sorted- or in vitro differentiated Tregs increasedinvasiveness of 4T1 cells both in vitro and in vivo, promotingE-cadherin downregulation and Snail up-regulation (p=0.05).Accordingly, we observed a progestin-driven expansion of theCD44+ stem cell-like population that formed mamospheres withaugmented tumorigenicity and invasive phenotype. Our findingshighlight the relevance of progestins in modulating immunoregulatorycheckpoints in the tumor microenvironment and suggest amechanism through which Tregs could directly promote a metastaticand aggressive phenotype on tumor cells.