Huang Shuang, Zhou Nianxin, Zhao Linjie, Gimple Ryan C, Ahn Young Ha, Zhang Peidong, Wang Wei, Shao Bin, Yang Jingyun, Zhang Qian, Zhao Sai, Jiang Xuehan, Chen Zhiwei, Zeng Yangfan, Hu Hongbo, Gustafsson Jan-Åke, Zhou Shengtao
Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China.
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, CA, USA.
iScience. 2020 Aug 12;23(9):101458. doi: 10.1016/j.isci.2020.101458. eCollection 2020 Sep 25.
The emerging immune checkpoint blockade (ICB) therapy has ushered the cancer therapeutics field into an era of immunotherapy. Although ICB treatment provides remarkable clinical responses in a subset of patients with cancer, this regimen fails to extend survival in a large proportion of patients. Here, we found that a combined treatment of estrogen receptor beta (ERβ) agonist and PD-1 antibody treatment improved therapeutic efficacy in mouse tumor models, compared with monotherapies, by reducing infiltration of myeloid-derived suppressor cells (MDSCs) and increasing CD8 T cells in tumors. Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R MDSC chemotaxis and blockade of CSF1R demonstrated similar therapeutic effects as ERβ activation . Collectively, our study proved combined treatment of ERβ agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.
新兴的免疫检查点阻断（ICB）疗法已将癌症治疗领域带入免疫治疗时代。尽管ICB治疗在一部分癌症患者中产生了显著的临床反应，但该方案在很大一部分患者中未能延长生存期。在这里，我们发现，与单一疗法相比，雌激素受体β（ERβ）激动剂和PD-1抗体联合治疗通过减少髓源性抑制细胞（MDSC）的浸润并增加肿瘤中的CD8 T细胞，提高了小鼠肿瘤模型的治疗效果。从机制上讲，LY500307治疗减少了肿瘤来源的CSF1，并减少了CSF1R MDSC在肿瘤床中的浸润。肿瘤细胞释放的CSF1诱导CSF1R MDSC趋化，而阻断CSF1R显示出与ERβ激活相似的治疗效果。总体而言，我们的研究证明，ERβ激动剂和PD-1抗体联合治疗可减少肿瘤中MDSC的浸润，并增强肿瘤对ICB治疗的反应。
