Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13+CD103+CD8+ Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy

Chupeng Hu; Wenhua You; Deyuan Kong; Yedi Huang; JinYing Lu; Mengya Zhao; Yu Jin; Rui Peng; Dong Hua; Dong-Ming Kuang; Yun Chen

doi:10.1053/j.gastro.2023.10.022

Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13⁺CD103⁺CD8⁺ Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy

Gastroenterology. 2023 Oct 29:S0016-5085(23)05198-3. doi: 10.1053/j.gastro.2023.10.022. Online ahead of print.

Authors

Chupeng Hu¹, Wenhua You², Deyuan Kong², Yedi Huang², JinYing Lu², Mengya Zhao², Yu Jin², Rui Peng³, Dong Hua⁴, Dong-Ming Kuang⁵, Yun Chen⁶

Affiliations

¹ Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi, China; Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; The Affiliated Huai'an No. 1 People's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
² Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Nanjing Medical University, Nanjing, China.
³ Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
⁴ The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi, China.
⁵ MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangdong, China.
⁶ Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi, China; Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Nanjing Medical University, Nanjing, China; The Affiliated Huai'an No. 1 People's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: chenyun@njmu.edu.cn.

PMID: 38445519
DOI: 10.1053/j.gastro.2023.10.022

Abstract

Background & aims: Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances antitumor immunity is not well understood. The present study aimed to investigate the underlying cross talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy.

Methods: Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13)⁺ cluster of differentiation (CD)103⁺CD8⁺ Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13⁺CD103⁺CD8⁺ Trm cells was determined in vitro and in vivo. The effect of CXCL13⁺CD103⁺CD8⁺ Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy.

Results: The presence of TLS and CXCL13⁺CD103⁺CD8⁺ Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103⁺CD8⁺ Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103⁺CD8⁺ Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103⁺CD8⁺ Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13⁺CD103⁺CD8⁺ Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner.

Conclusions: This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13⁺CD103⁺CD8⁺ Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13⁺CD103⁺CD8⁺ Trm cells for advancing immunotherapy strategies in GC.

Keywords: CXCL13(+)CD103(+)CD8(+) Trm Cell; Gastric Cancer; Immunotherapy; TNFR2; Tertiary Lymphoid Structure.