INVESTIGADORES
RABINOVICH Gabriel Adrian
artículos
Título:
Enhanced antitumor immunity via endocrine therapy prevents mammary tumor relapse and increases immune checkpoint blockade sensitivity
Autor/es:
GONZALO SEQUEIRA; ANA SAHORES; TOMAS DALOTTO MORENO; RAMIRO PERROTTA; GABRIELA PATACCINI; SILVIA VANZULLI ; MARIA L. POLO; DEREK RADISKY; CAROL SARTORIUS; VIRGINIA NOVARO; CAROLINE LAMB; GABRIEL RABINOVICH; MARIANA SALATINO; CLAUDIA LANARI
Revista:
CANCER RESEARCH
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Lugar: Philadelphia; Año: 2021
ISSN:
0008-5472
Resumen:
The role of active antitumor immunity in hormone receptor positive (HR+)breast cancer has been historically underlooked. The aim of this study was todetermine the contribution of the immune system to antiprogestin-induced tumorgrowth inhibition using a hormone-dependent breast cancer model. BALB/c-GFP+bone marrow (BM) cells were transplanted into immunodeficient NSG mice togenerate an immunocompetent NSG/BM-GFP+ (NSG-R) mouse model. Treatmentwith the antiprogestin Mifepristone (MFP) inhibited growth of 59-2-HI tumors withsimilar kinetics in both animal models. Interestingly, MFP treatment reshaped thetumor microenvironment, enhancing the production of proinflammatory cytokinesand chemokines. Tumors in MFP-treated immunocompetent mice showedincreased infiltration of F4/80+ macrophages, NK, and CD8 T cells, displaying acentral memory phenotype. Mechanistically, MFP induced immunogenic cell deathin vivo and in vitro, as depicted by the expression and subcellular localization of thealarmins calreticulin and HMGB-1 and the induction of an immunogenic cell deathgene program. Moreover, MFP-treated tumor cells efficiently activated immaturedendritic cells, evidenced by enhanced expression of MHC-II and CD86, andinduced a memory T cell response, attenuating tumor onset and growth after rechallenge.Finally, MFP treatment increased the sensitivity of HR+ 59-2-HI tumor toPD-L1 blockade, suggesting that antiprogestins may improve immunotherapyresponse rates. These results contribute to a better understanding of themechanisms underlying the antitumor effect of hormonal treatment and the rationaldesign of therapeutic combinations based on endocrine and immunomodulatoryagents in HR+ breast cancer.