Differential T cell clonal dynamics underlie outcomes to frontline chemoimmunotherapy in advanced gastric cancer

The addition of aPD1 to 5-FU/platinum in advanced gastric cancer (GC) yields variable responses. To understand cooperativity between chemotherapy and immunotherapy, we previously reported a phase II trial sequentially adding pembrolizumab to 5-FU/platinum. In this study, we use single-cell RNA- and TCR-sequencing to analyze 66,813 T cells from primary tumor biopsies pre-treatment, post-chemotherapy, and post-immunotherapy in 33 patients. We observed greater abundance, persistence, and recruitment of T cells with predicted tumor-reactivity in patients with prolonged progression-free survival (slow progressors). Increased B cell abundance and predicted B cell to T cell interactions supported T cell memory and co-stimulation, providing a mechanism for increased abundance and persistence of progenitor-exhausted and tumor-reactive T cells in slow progressors. T cell clones emerging in the tumor after immunotherapy were in the blood before treatment only in slow progressors. Our study thus highlights pre-treatment and early chemotherapy-induced T cell dynamics and B cell to T cell interactions that may drive durable response to chemoimmunotherapy in GC.