Macrophages facilitate tumor cell PD‐L1 expression via an IL‐1β‐centered loop to attenuate immune checkpoint blockade
Cheng Xu,
Yu Xia,
Bai‐Wei Zhang,
Emmanuel Kwateng Drokow,
Hua‐Yi Li,
Sen Xu,
Zhen Wang,
Si‐Yuan Wang,
Ping Jin,
Tian Fang,
Xiao‐Ming Xiong,
Pu Huang,
Ning Jin,
Jia‐Hong Tan,
Qing Zhong,
Yu‐Xin Chen,
Qi Zhang,
Yong Fang,
Fei Ye,
Qing‐Lei Gao
Affiliations
Cheng Xu
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Yu Xia
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Bai‐Wei Zhang
Department of Neurosurgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Emmanuel Kwateng Drokow
Department of Radiation Oncology Zhengzhou University People's Hospital & Henan Provincial People's Hospital Zhengzhou China
Hua‐Yi Li
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Sen Xu
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Zhen Wang
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Si‐Yuan Wang
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Ping Jin
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Tian Fang
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Xiao‐Ming Xiong
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Pu Huang
Department of Obstetrics and Gynecology The Second Affiliated Hospital Wenzhou Medical University Wenzhou China
Ning Jin
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Jia‐Hong Tan
Department of Obstetrics and Gynecology The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology Kunming China
Qing Zhong
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Yu‐Xin Chen
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Qi Zhang
Department of Plastic and Cosmetic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Yong Fang
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Fei Ye
Department of Neurosurgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Qing‐Lei Gao
Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
Abstract Tumor‐associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)‐1β was among the most abundant cytokines within the in vitro tumor‐macrophage coculture system, and enhanced IL‐1β expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL‐1β mediated immunosuppression during tumor‐TAMs crosstalk. Mechanistically, we demonstrated that IL‐1β significantly boosted programmed death‐ligand 1 (PD‐L1) expression in tumor cells via the activation of the nuclear factor‐κb signaling cascade. Specifically, IL‐1β released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation‐dependent manner. IL‐1β sustained and intensified immunosuppression by promoting C‐C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL‐1β neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti‐PD‐L1 antibody in tumor‐bearing mouse models. Together, this study presents an IL‐1β‐centered immunosuppressive loop between TAMs and tumor cells, highlighting IL‐1β as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.