Immunotherapy for diffuse gastric cancer: challenges and new avenues

Abstract

In recent years, several large clinical trials have demonstrated the survival benefits of immunotherapies, mainly immune checkpoint inhibitors (ICIs), in patients with gastric cancer (GC). However, not every GC patient responds equally to immunotherapy. Compared with patients with intestinal GC (IGC), patients with diffuse GC (DGC) are less likely to obtain a survival benefit from the currently approved ICIs. This histological determinant of immunotherapy efficacy in GC has attracted less attention, exposing some patients with DGC to unnecessary risks. Limited data suggest that the cold tumor immune microenvironment, which is shaped by histological and molecular characteristics, challenges the success of immunotherapy in patients with GC. Here, we review the possible mechanisms of resistance and propose new avenues to overcome resistance to immunotherapy in DGC.

Fig. 1. Histological and molecular barriers to effective immunotherapy in diffuse gastric cancer.

Diffuse gastric cancer (DGC) exhibits many histological and molecular features, including (A) insufficient antigenicity and antigen presentation, (B) disruption of interferon-γ signaling, (C) activation of oncogenic signaling, and (D) stroma barriers, which lead to a cold tumor immune microenvironment (TIME), which is less responsive to immunotherapy. AKT protein kinase B, ARHGAP Rho GTPase-activating protein, CAFs cancer-associated fibroblasts, CLDN18 claudin 18, EMT epithelial–mesenchymal transition, ER endoplasmic reticulum, INFγ interferon γ, INFγR interferon γ receptor, JAK Janus kinase, MHC major histocompatibility complex, PD-L1 programmed death-ligand 1, PI3K phosphoinositide 3-kinase, SMAD suppressor of mothers against decapentaplegic homolog, STAT signal transducer and activator of transcription, TAMs tumor-associated macrophages, TGF-β transforming growth factor-β, YAP1 Yes-associated protein 1.

Fig. 2. New avenues to improve the efficacy of immunotherapy in diffuse gastric cancer.

New avenues, including (A) promoting the progression of the cancer-immunity cycle, (B) biomarker-directed patient stratification, and (C) alternative immunotherapy strategies and targets, may have the potential to improve the efficacy of immunotherapy in diffuse gastric cancer (DGC) patients. APC antigen-presenting cell, CAF cancer-associated fibroblast, CAR chimeric antigen receptor, FGFR fibroblast growth factor receptor, HIPEC hyperthermic intraperitoneal chemotherapy, ICD immunogenic cancer cell death, mAbs monoclonal antibodies, MET hepatocyte growth factor, MMR mismatch repair, MSI microsatellite instability, PD-L1 programmed death-ligand 1, TGF-β transforming growth factor-β, TMB tumor mutation burden.