Enhanced Antitumor Immunity via Endocrine Therapy Prevents Mammary Tumor Relapse and Increases Immune Checkpoint Blockade Sensitivity

Abstract

The role of active antitumor immunity in hormone receptor–positive (HR+) 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-GFP+ bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFP+ (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 F4/80+ 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 HR+ 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 HR+ 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.

The gold complex auranofin: new perspectives for cancer therapy

“…Thus, adding anti-PD-1 or anti-PD-L1 antibodies on the top of auranofin/cisplatin combination therapy seems a rational combinational therapeutic approach. This idea is further supported by recent literature showing that breast cancer tissues were sensitive to mifepristone-an antiprogestin and antiglucocorticoid agent [140], which was able to induce ICD and thus synergize with PD-L1 blockade [141]. We previously reported that the anti-cancer effects of mifepristone [142,143] were associated with the induction of proteotoxic ER stress [144], a pathway needed to be active for ICD to succeed.…”

Immunogenic cell stress and death

“…Indeed, not all cell-death inducers can elicit the intracellular stress pathways that operate upstream of DAMP release in dying cancer cells (see below). Clinically actionable ICD inducers include specific conventional chemotherapeutics (for example, cyclophosphamide, anthracyclines, oxaliplatin and other platinum derivatives, but not cisplatin) 10,[36][37][38][39][40] , RT 41 and select targeted anticancer agents (for example, bortezomib, crizotinib) [42][43][44][45][46][47][48] , as well as some variants of endocrine therapy 49 , extracorporeal photochemotherapy 50 , photodynamic therapy (PDT) [51][52][53][54] and oncolytic virotherapy 55,56 . As a general principle, the release of DAMPs by malignant cells succumbing to these agents involves either alterations of the cell surface (for example, owing to the translocation of intracellular proteins to the external leaflet of the plasma membrane) or changes of the…”

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

“…On the other hand, progestagens reconfigure the breast cancer microenvironment, inducing the preferential expansion of myeloid-derived suppressor cells in the spleen and bone marrow of tumor-bearing mice [ 355 ]. Furthermore, anti-progesterone treatments enhance the anti-tumor immune response and increase sensitivity to the PD-L1 blockade in breast cancers [ 356 ]. It is worth noting that progesterone regulates galectin-1 expression in some experimental settings [ 357 , 358 ].…”