免疫检查点抑制剂+MDSC阻断剂:最恶性前列腺癌的克星
  • 大多数晚期前列腺癌患者经过雄激素去势治疗后复发,持续进展为致死性的、去势抵抗性前列腺癌(mCRPC);
  • mCRPC大多对免疫检查点抑制剂治疗原发耐药,循环血中髓系抑制细胞 (MDSCs)的丰度与前列腺癌患者的前列腺特异性抗原水平及转移相关;
  • 制备嵌合型 mCRPC小鼠模型,免疫检查点抑制剂和MDSC靶向治疗联合时,原发性和转移性CRPC均有明显的缓解;
  • 联合治疗的疗效,源于上调了白介素-1受体,拮抗和抑制了前列腺癌细胞分泌的MDSC刺激因子。
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Nature [IF:42.778]

Effective combinatorial immunotherapy for castration-resistant prostate cancer

去势抵抗性前列腺癌联合免疫治疗的疗效

10.1038/nature21676

2017-03-30, Letter

Abstract & Authors:展开

Abstract:收起
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.

First Authors:
Xin Lu

Correspondence Authors:
Y Alan Wang,Ronald A DePinho

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

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