Effective combinatorial immunotherapy for castration-resistant prostate cancer

被引:426
作者
Lu, Xin [1 ,6 ]
Horner, James W. [2 ]
Paul, Erin [2 ]
Shang, Xiaoying [1 ]
Troncoso, Patricia [3 ]
Deng, Pingna [1 ]
Jiang, Shan [2 ]
Chang, Qing [2 ]
Spring, Denise J. [1 ]
Sharma, Padmanee [4 ]
Zebala, John A. [5 ]
Maeda, Dean Y. [5 ]
Wang, Y. Alan [1 ]
DePinho, Ronald A. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA
[5] Syntrix Biosyst Inc, Auburn, WA 98001 USA
[6] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA
基金
美国国家卫生研究院;
关键词
TYROSINE KINASE INHIBITOR; SUPPRESSOR-CELLS; DOUBLE-BLIND; CHECKPOINT BLOCKADE; PHASE-III; DASATINIB; PLACEBO; MICROSATELLITE; IPILIMUMAB; SENESCENCE;
D O I
10.1038/nature21676
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(3-5), 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(7-9). 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.
引用
收藏
页码:728 / +
页数:18
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