2. Academic Validation
  3. Macrophages facilitate tumor cell PD-L1 expression via an IL-1β-centered loop to attenuate immune checkpoint blockade

Macrophages facilitate tumor cell PD-L1 expression via an IL-1β-centered loop to attenuate immune checkpoint blockade

  • MedComm (2020). 2023 Mar 30;4(2):e242. doi: 10.1002/mco2.242.
Cheng Xu 1 2,  Yu Xia 1 2,  Bai-Wei Zhang 3,  Emmanuel Kwateng Drokow 4,  Hua-Yi Li 1 2,  Sen Xu 1 2,  Zhen Wang 1 2,  Si-Yuan Wang 1 2,  Ping Jin 1 2,  Tian Fang 1 2,  Xiao-Ming Xiong 1 2,  Pu Huang 5,  Ning Jin 1 2,  Jia-Hong Tan 6,  Qing Zhong 1 2,  Yu-Xin Chen 1 2,  Qi Zhang 7,  Yong Fang 1 2,  Fei Ye 3,  Qing-Lei Gao 1 2
Affiliations

Affiliations

  • 1 Department of Gynecological Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.
  • 2 National Clinical Research Center for Obstetrics and Gynecology Cancer Biology Research Center (Key Laboratory of the Ministry of Education) Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.
  • 3 Department of Neurosurgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.
  • 4 Department of Radiation Oncology Zhengzhou University People's Hospital & Henan Provincial People's Hospital Zhengzhou China.
  • 5 Department of Obstetrics and Gynecology The Second Affiliated Hospital Wenzhou Medical University Wenzhou China.
  • 6 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.
  • 7 Department of Plastic and Cosmetic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.
PMID: 37009412 DOI: 10.1002/mco2.242
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.

Keywords

immune checkpoint blockade; interleukin‐1β; programmed death‐ligand 1; tumor‐associated macrophages; tumor‐immune microenvironment.

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