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.
Department of Immunology, School of Basic Medical Sciences, Wuxi Medical Center, Nanjing Medical University, Nanjing, China.
Gastroenterology. 2024 Jun;166(6):1069-1084. doi: 10.1053/j.gastro.2023.10.022. Epub 2023 Oct 29.
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.
Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13) cluster of differentiation (CD)103CD8 Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13CD103CD8 Trm cells was determined in vitro and in vivo. The effect of CXCL13CD103CD8 Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy.
The presence of TLS and CXCL13CD103CD8 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 CD103CD8 Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103CD8 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 CD103CD8 Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13CD103CD8 Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner.
This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13CD103CD8 Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13CD103CD8 Trm cells for advancing immunotherapy strategies in GC.
尽管在许多实体恶性肿瘤中，三级淋巴结构（TLS）的存在与免疫治疗的阳性反应相关，但 TLS 增强抗肿瘤免疫的机制尚不清楚。本研究旨在探讨 TLS 内 B 细胞与组织驻留记忆 T（Trm）细胞之间的潜在交叉对话回路，并了解它们在免疫治疗背景下的作用。
对胃癌（GC）患者肿瘤组织中的 TLS 和趋化因子（C-X-C 基序）配体 13（CXCL13）CD103CD8 Trm 细胞进行免疫染色和苏木精和伊红（H&E）染色。在体外和体内确定 B 细胞与 CXCL13CD103CD8 Trm 细胞之间的通讯机制。通过抗程序性细胞死亡蛋白（PD）-1 治疗评估 CXCL13CD103CD8 Trm 细胞抑制肿瘤生长的作用。
肿瘤组织中 TLS 和 CXCL13CD103CD8 Trm 细胞的存在有利于 GC 患者对抗 PD-1 治疗的更好反应。此外，我们的研究发现，激活的 B 细胞增强了 CD103CD8 Trm 细胞中 CXCL13 和颗粒酶 B 的分泌。从机制上讲，B 细胞通过淋巴毒素-α/肿瘤坏死因子受体 2（TNFR2）轴促进 CD103CD8 Trm 细胞的糖酵解，而雷帕霉素信号通路的机制靶点在这一过程中对 CD103CD8 Trm 细胞的糖酵解起着关键作用。此外，TLS 和 CXCL13CD103CD8 Trm 细胞的存在与 TNFR2 依赖性抗 PD-1 治疗的强反应相关。
这项研究进一步揭示了 TLS 相关 B 细胞与 CXCL13CD103CD8 Trm 细胞之间细胞通讯在抗肿瘤免疫中的关键作用，为淋巴毒素-α/TNFR2 轴在 CXCL13CD103CD8 Trm 细胞中的潜在用途提供了有价值的见解，以推进 GC 中的免疫治疗策略。
