Journal Article

Effective combinatorial immunotherapy for castration-resistant prostate cancer

Spring, Denise J., Sharma, Padmanee, Deng, Pingna, Paul, Erin, Maeda, Dean Y., Wang, Y. Alan, DePinho, Ronald A., Shang, Xiaoying, Zebala, John A., Jiang, Shan, Chang, Qing, Horner, James W., Lu, Xin, Troncoso, Patricia

2017

Overview

A new chimaeric mouse model of metastatic castration-resistant prostate cancer to efficiently test combination therapies in an autochthonous setting. Combination cancer therapies Metastatic castration-resistant prostate cancer (mCRPC) does not show strong responses to immunotherapies, such as immune checkpoint blockade (ICB), which have produced durable therapeutic responses in other cancer types. The authors develop a new chimaeric mouse model of mCRPC in which they test different combinations of immunotherapies, including ICB, and targeted therapies. They found that the most efficacious combinations were those that depleted myeloid-derived suppressor cells, suggesting the potential clinical relevance of this cell population. A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC) 1 . Immune checkpoint blockade 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 types 2 . However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade 3 , 4 , 5 , motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion 6 . The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer 7 , 8 , 9 . Mouse models of prostate cancer show that MDSCs (CD11b + Gr1 + ) promote tumour initiation 10 and progression 11 . These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric 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-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1059 / 631/67/589 / 64 / 64/60 / Analysis / Anilides - pharmacology / Anilides - therapeutic use / Animals / Cancer metastasis / Cancer therapies / Care and treatment / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Chimera / Cytokines - immunology / Cytokines - metabolism / Disease Models, Animal / Drug Synergism / Female / Humanities and Social Sciences / Humans / Imidazoles - pharmacology / Imidazoles - therapeutic use / Immunotherapy / Immunotherapy - methods / letter / Lymphocytes / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Male / Mice / Molecular Targeted Therapy / multidisciplinary / Myeloid-Derived Suppressor Cells - cytology / Myeloid-Derived Suppressor Cells - drug effects / Myeloid-Derived Suppressor Cells - immunology / Patient outcomes / Phosphatidylinositol 3-Kinases - antagonists & inhibitors / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - immunology / Prostatic Neoplasms, Castration-Resistant - pathology / Prostatic Neoplasms, Castration-Resistant - therapy / Pyridines - pharmacology / Pyridines - therapeutic use / Quinolines - pharmacology / Quinolines - therapeutic use / Science / Signal Transduction - drug effects / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors