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Effective combinatorial immunotherapy for castration-resistant prostate cancer

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

Nature (London), 2017-03-30, Vol.543 (7647), p.728-732 [Peer Reviewed Journal]

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Title:
Effective combinatorial immunotherapy for castration-resistant prostate cancer
Author: Lu, Xin ; Horner, James W ; Paul, Erin ; Shang, Xiaoying ; Troncoso, Patricia ; Deng, Pingna ; Jiang, Shan ; Chang, Qing ; Spring, Denise J ; Sharma, Padmanee ; Zebala, John A ; Maeda, Dean Y ; Wang, Y Alan ; DePinho, Ronald A
Subjects: Anilides - therapeutic use ; Immunotherapy - methods ; Humans ; Prostatic Neoplasms, Castration-Resistant - immunology ; Male ; Myeloid-Derived Suppressor Cells - drug effects ; Molecular Targeted Therapy ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Prostatic Neoplasms, Castration-Resistant - pathology ; Quinolines - pharmacology ; Myeloid-Derived Suppressor Cells - cytology ; Prostatic Neoplasms, Castration-Resistant - therapy ; Female ; Imidazoles - therapeutic use ; Cytokines - immunology ; Disease Models, Animal ; Pyridines - therapeutic use ; Tumor Microenvironment - drug effects ; Myeloid-Derived Suppressor Cells - immunology ; Cytokines - metabolism ; Imidazoles - pharmacology ; Lymphocytes, Tumor-Infiltrating - drug effects ; Drug Synergism ; Tumor Microenvironment - immunology ; Animals ; Signal Transduction - drug effects ; CD8-Positive T-Lymphocytes - drug effects ; Anilides - pharmacology ; Mice ; Pyridines - pharmacology ; Quinolines - therapeutic use ; CD8-Positive T-Lymphocytes - immunology ; Chimera ; Lymphocytes, Tumor-Infiltrating - immunology ; Care and treatment ; Metastasis ; Prostate cancer ; Analysis ; Immunotherapy ; Patient outcomes ; Index Medicus
Is Part Of: Nature (London), 2017-03-30, Vol.543 (7647), p.728-732
Description: 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). 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. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, 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. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b Gr1 ) promote tumour initiation and progression. 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: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/nature21676
PMID: 28321130

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Effective combinatorial immunotherapy for castration-resistant prostate cancer

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

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