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

作者：Samuel J. Wright, Sarah Kang, Minae An, You Jeong Heo, Milan Parikh, Lynn Bi, Hyuk Lee, Graydon Moorhead, Nicholas J. Haradhvala, Sung Hee Lim, Seung Tae Kim, Gad Getz, Nir Hacohen, Jeeyun Lee, Arnav Mehta, Samuel J. Klempner, Ryan J. Park · 发表于：Cell Reports Medicine · 年份：2026 · DOI：10.1016/j.xcrm.2026.102910 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune Cell Function and Interaction、Immune cells in 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.