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Effective Combinatorial Immunotherapy for Castration Resistant Prostate Cancer #MMPMID28321130
Lu X; Horner JW; Paul E; Shang X; Troncoso P; Deng P; Jiang S; Chang Q; Spring DJ; Sharma P; Zebala JA; Maeda DY; Wang YA; DePinho RA
Nature 2017[Mar]; 543 (7647): 728-32 PMID28321130show ga
A significant fraction of advanced prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC)1. Immune checkpoint blockade (ICB) using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types2. However, mCRPC showed overwhelming de novo resistance to ICB3?5, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumor immune evasion6. Circulating MDSC abundance correlates with PSA levels and metastasis in PCa patients7?9. Mouse models of PCa show that MDSCs (CD11b+ Gr1+) promote tumor initiation10 and progression11. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. Here we developed a novel chimeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumor activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when ICB was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of IL-1ra and suppression of MDSC-promoting cytokines secreted by PCa cells. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC.
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Nature 2017 ; 543 (7647): 728-32
