Vitamin B5 supports anti-PD1 response in HER2-positive gastric cancer and enhances interaction between naïve B cells and T cells.

The cellular mechanisms underlying HER2-positive gastric cancer (HER2+ GC) responses to immunochemotherapy remain underexplored. Here, we perform longitudinal single-cell RNA-sequencing with paired TCR/BCR profiling on HER2+ and HER2-negative gastric cancer (HER2- GC) pre- and post-treatment to find dynamic immune remodeling during. Pre-treatment HER2+ GC displays an immunogenic microenvironment enriched with tumor-reactive T and B cells compared to HER2- GC. Following immunochemotherapy (anti-PD-1, XELOX/FOLFOX and anti-HER2), HER2+ GC display clonal expansions of tumor-reactive T cells, increased memory B cell differentiation, enhanced naïve B cell recruitment, and enriched B-T cell interaction. Mechanistically, vitamin B5 promotes human T cell proliferation in coculture with naïve B cells. Notably, B5 biosynthesis is enriched in tumor-infiltrating naïve B cells in GC patient samples, and serum B5 concentration is elevated in the HER2+PD-L1+ subset. In vivo, vitamin B5 supplementation boosts anti-PD-1 responses in female mice bearing subcutaneous cancers. Our data thus demonstrate a critical function for naïve B cells in immunochemotherapy response in HER2+ GC, and also implicate vitamin B5 supplementation for potentiating immune checkpoint blockade.