Phase 2 trial links early monocyte elevation to response in gastric cancer immunotherapy

Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy has reshaped metastatic gastric cancer (GC) treatment, improving response rate, progression-free survival, and overall survival. We aimed to explore circulating immune cells and elucidate the mechanisms underlying the therapeutic effects of pembrolizumab and capecitabine/oxaliplatin (XELOX) in patients with metastatic GC. Potential immune mechanisms in GC tumors were retrospectively examined among patients from our phase 2 chemoimmunotherapy trial. Peripheral blood samples from patients with GC undergoing first-line pembrolizumab plus XELOX therapy were monitored using high-dimensional cytometry. Matched paired-tissue single-cell RNA-seq data were analyzed. Samples were collected from 24 patients at baseline, after one cycle of XELOX (FU1), and 18 weeks after pembrolizumab addition (FU2). Natural killer cell (CD3-NCAM +) and myeloid cell (CD11c + or CD14 +) subsets increased during chemoimmunotherapy.-At FU1, the proportion of PBMC monocytes was significantly higher in responders compared to non-responders. Consistent with the increase in monocyte-derived macrophages (M1-like) in paired tissues, monocytes in peripheral blood mononuclear cells increased at FU1. Immunosenescence score revealed recently mobilized monocytes infiltrating the tumor bed after chemotherapy. Gene expression analysis showed significantly upregulated CXCL8, CCL3, and CCL4 in FU1 responders. Early elevation of circulating monocytes correlated with better survival. After adding pembrolizumab, memory CD8 (CD3 + CD8 + CD27 + CD28 + CD45RO +) T cells increased in responders compared to non-responders. Our results elucidate the serial immunological landscape underpinning favorable responses to first-line ICI plus chemotherapy in patients with gastric cancer. Early distinct changes in blood myeloid cells during chemotherapy can be used to assess clinical response.