Tertiary lymphoid structure-associated B cells enhance CXCL13⁺CD103⁺CD8⁺Trm cell response to PD-1 blockade in gastric cancer.

Abstract

Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances anti-tumor 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 hematoxylin and eosin staining of TLS and CXCL13⁺CD103⁺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 both in vitro and in vivo. The effect of CXCL13⁺CD103⁺CD8⁺Trm cells in suppressing tumor growth was evaluated through anti-PD-1 therapy. The presence of TLS and CXCL13⁺CD103⁺CD8⁺Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in GC patients. 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 Alpha (LTα)/Tumor necrosis factor receptor 2 (TNFR2) axis, and the mTOR 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. This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13⁺CD103⁺CD8⁺Trm cells in anti-tumor immunity, providing valuable insights into the potential utilization of the LTα/TNFR2 axis within CXCL13⁺CD103⁺CD8⁺Trm cells for advancing immunotherapy strategies in GC.