Tertiary lymphoid structure-associated B cells enhance CXCL13CD103CD8Trm cell response to PD-1 blockade in gastric cancer.

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 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.

METHODS

Immunostaining and hematoxylin and eosin staining of TLS and CXCL13CD103CD8Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13CD103CD8Trm cells was determined both in vitro and in vivo. The effect of CXCL13CD103CD8Trm cells in suppressing tumor growth was evaluated through anti-PD-1 therapy.

RESULTS

The presence of TLS and CXCL13CD103CD8Trm 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 CD103CD8Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103CD8Trm cells through the Lymphotoxin Alpha (LTα)/Tumor necrosis factor receptor 2 (TNFR2) axis, and the mTOR signaling pathway played a critical role in CD103CD8Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13CD103CD8Trm 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 CXCL13CD103CD8Trm cells in anti-tumor immunity, providing valuable insights into the potential utilization of the LTα/TNFR2 axis within CXCL13CD103CD8Trm cells for advancing immunotherapy strategies in GC.