Enhanced antitumor immunity via endocrine therapy prevents mammary tumor relapse and increases immune checkpoint blockade sensitivity

SEQUEIRA, GONZALO R.; SAHORES, ANA; DALOTTO-MORENO, TOMAS; PERROTTA, RAMIRO M.; PATACCINI, GABRIELA; VANZULLI, SILVIA I.; POLO, MARÍA L.; RADISKY, DEREK C.; SARTORIUS, CAROL A.; NOVARO, VIRGINIA; LAMB, CAROLINE A.; RABINOVICH, GABRIEL A.; SALATINO, MARIANA; LANARI, CLAUDIA

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2021 vol. 81 p. 1375 - 1387

0008-5472

The role of active antitumor immunity in hormone receptor–positive (HRþ) breast cancer has been historically underlooked. The aim of this study was to determine the contribution of the immune system to antiprogestin-induced tumor growth inhibition using a hormone-dependent breast cancer model. BALB/c-GFPþ bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFPþ (NSG-R) mouse model. Treatment with the antiprogestin mifepristone (MFP) inhibited growth of 59–2-HI tumors with similar kinetics in both animal models. Interestingly, MFP treatment reshaped the tumor microenvironment, enhancing the production of proinflammatory cytokines and chemokines. Tumors in MFP-treated immunocompetent mice showed increased infiltration of F4/80þ macrophages, natural killer, and CD8 T cells, displaying a central memory phenotype. Mechanistically, MFP induced immunogenic cell death (ICD) in vivo and in vitro, as depicted by the expression and subcellular localization of the alarmins calreticulin and HMGB-1 and the induction of an ICD gene program. Moreover, MFP-treated tumor cells efficiently activated immature dendritic cells, evidenced by enhanced expression of MHC-II and CD86, and induced a memory T-cell response, attenuating tumor onset and growth after re-challenge. Finally, MFP treatment increased the sensitivity of HRþ 59–2-HI tumor to PD-L1 blockade, suggesting that antiprogestins may improve immunotherapy response rates. These results contribute to a better understanding of the mechanisms underlying the antitumor effect of hormonal treatment and the rational design of therapeutic combinations based on endocrine and immunomodulatory agents in HRþ breast cancer. Significance: Antiprogestin therapy induces immunogenic tumor cell death in PRA-overexpressing tumors, eliciting an adaptive immune memory response that protects mice from future tumor recurrence and increases sensitivity to PD-L1 blockade. Graphical Abstract: http://cancerres.aacrjournals.org/content/ canres/81/5/1375/F1.large.jpg.