Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13CD103CD8 Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy.

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)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.

RESULTS

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.

CONCLUSIONS

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.