Pharmacological Activation of Estrogen Receptor Beta Overcomes Tumor Resistance to Immune Checkpoint Blockade Therapy
Shuang Huang,
Nianxin Zhou,
Linjie Zhao,
Ryan C. Gimple,
Young Ha Ahn,
Peidong Zhang,
Wei Wang,
Bin Shao,
Jingyun Yang,
Qian Zhang,
Sai Zhao,
Xuehan Jiang,
Zhiwei Chen,
Yangfan Zeng,
Hongbo Hu,
Jan-Åke Gustafsson,
Shengtao Zhou
Affiliations
Shuang Huang
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
Nianxin Zhou
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
Linjie Zhao
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, CA, USA
Ryan C. Gimple
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, CA, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
Young Ha Ahn
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
Peidong Zhang
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
Wei Wang
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
Bin Shao
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P. R. China
Jingyun Yang
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
Qian Zhang
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
Sai Zhao
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
Xuehan Jiang
College of Life Science, Sichuan University, Chengdu, P. R. China
Zhiwei Chen
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
Yangfan Zeng
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
Hongbo Hu
Department of Rheumatology and Immunology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, P. R. China
Jan-Åke Gustafsson
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, U.S.A; Department of Biosciences and Nutrition at NOVUM, Karolinska Institute, Solna, Sweden; Corresponding author
Shengtao Zhou
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; Corresponding author
Summary: 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 in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERβ activation in vivo. 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.
