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

Abstract

The addition of anti-programmed cell death protein 1 (aPD-1) to 5-fluorouracil (5-FU)/platinum in advanced gastric cancer (GC) yields variable responses. To understand chemotherapy-immunotherapy cooperativity, we previously reported a phase II trial sequentially adding pembrolizumab to 5-FU/platinum. In this study, we use single-cell RNA sequencing and T cell receptor (TCR) sequencing to analyze 66,813 T cells from primary tumor biopsies pre-treatment, post-chemotherapy, and post-immunotherapy in 33 patients. We observe greater abundance, persistence, and recruitment of T cells with transcriptionally predicted tumor-reactivity in patients with prolonged progression-free survival (slow progressors). Increased B cell abundance and predicted B cell to T cell interactions support 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 are present in the blood before treatment only in slow progressors. We thus highlight mechanisms that may drive durable responses to chemoimmunotherapy in GC.