JAK inhibitor overcomes resistance to immune checkpoint inhibitor treatment in gastric cancer peritoneal dissemination in mouse

ABSTRACT: Objective Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC. Design The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination, was assessed using the YTN16 peritoneal dissemination tumor model mice. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A JAK inhibitor (JAKi) was introduced based on the pathway analysis results. Results Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8+ T cells. However, in mice resistant to dual ICI treatment, even with CD8+ T cell infiltration, most of the T cells exhibited exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the JAK-STAT pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8+ T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment. Conclusion Dual ICI treatment exerts its anti-tumor effects by increasing tumor- specific CD8+ T cell infiltration, and the addition of JAKi further improves ICI resistant by reshaping the immunosuppressive TME.

ORGANISM(S): Mus musculus

PROVIDER: GSE250238 | GEO | 2024/05/28

REPOSITORIES: GEO