Funding
Doris Duke Charitable Foundation (DDCF)
DeGregorio Family Foundation (DFF)
Stand Up To Cancer (SU2C)
Korea Health Industry Development Institute (KHIDI)
Sungkyunkwan University (SKKU)
ARTICLE ABSTRACT
Adding anti–programmed cell death protein 1 (anti–PD-1) to 5-fluorouracil (5-FU)/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy, we conducted a phase II first-line trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab, we transcriptionally profiled 358,067 single cells to identify evolving multicellular tumor microenvironment (TME) networks. Chemotherapy induced early on-treatment multicellular hubs with tumor-reactive T-cell and M1-like macrophage interactions in slow progressors. Faster progression featured increased MUC5A and MSLN containing treatment resistance programs in tumor cells and M2-like macrophages with immunosuppressive stromal interactions. After pembrolizumab, we observed increased CD8 T-cell infiltration and development of an immunity hub involving tumor-reactive CXCL13 T-cell program and epithelial interferon-stimulated gene programs. Strategies to drive increases in antitumor immune hub formation could expand the portion of patients benefiting from anti–PD-1 approaches.
The benefit of 5-FU/platinum with anti–PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti–PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti–PD-1 to potentiate T cell–driven responses. Differential TME hub development highlights features that underlie clinical outcomes.This article is featured in Selected Articles from This Issue, p. 695
