Effective combinatorial immunotherapy for castration-resistant prostate cancer.
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.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Xin
X
Lu
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
James W
JW
Horner
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Erin
E
Paul
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Xiaoying
X
Shang
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Patricia
P
Troncoso
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Pingna
P
Deng
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Shan
S
Jiang
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Qing
Q
Chang
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Denise J
DJ
Spring
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Padmanee
P
Sharma
Syntrix Biosystems, Inc., Auburn, Washington 98001, USA.
John A
JA
Zebala
Syntrix Biosystems, Inc., Auburn, Washington 98001, USA.
Dean Y
DY
Maeda
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Y Alan
YA
Wang
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ronald A
RA
DePinho
D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002678:Chimera; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D000072737:Myeloid-Derived Suppressor Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D064129:Prostatic Neoplasms, Castration-Resistant / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
D000813:Anilides; D016207:Cytokines; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011804:Quinolines; C558660:cabozantinib; C531198:dactolisib