Funding
Fujian third batch of "Innovation Star" talent project
Joint Funds for the innovation of science and Technology, Fujian Province
Science Fund for Distinguished Young Scholars of Fujian Province (福建省杰出青年自然科学基金)
National Natural Science Foundation of China (NSFC)
Fujian Medical University (FJMU)
Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province, China
Young eagle program for top talents for Fujian Province, China
Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare
ARTICLE ABSTRACT
Immune checkpoint blockade (ICB) therapies have achieved significant breakthroughs in cancer treatment over the past decade. However, ICB is largely ineffective in desert-type gastric cancer due to intrinsic tumor heterogeneity and a highly immunosuppressive tumor microenvironment (TME). Transforming tumors from an immunosuppressive state to an immunostimulatory state is a potential approach to enhance ICB response. In this study, we developed a chromosomal instability–subtype gastric cancer mouse model with an immunoactive TME and a stem cell–originated mouse-derived allograft model with an immunosuppressed TME to investigate mechanisms regulating the tumor immunophenotype and uncover therapeutic strategies to remodel the TME. Blocking β-catenin signaling attenuated the immunochemotherapeutic resistance of mouse-derived allograft tumors. The tyrosine kinase inhibitor apatinib reprogrammed the TME by increasing CD8+ T-cell and IGHA+ plasma cell infiltration and decreasing M2 macrophages, but apatinib also induced PD-L1 and CD80 expression in both human and mouse desert–type tumors. Oxaliplatin decreased the apatinib-induced expression of immune checkpoints and enhanced the antitumor efficacy of immunotherapy. A prospective clinical trial (NCT04195828) demonstrated that a neoadjuvant regimen of apatinib plus ICB and chemotherapy was effective in patients with desert-type gastric cancer. Collectively, these findings identify potential drug targets for immune desert–type gastric cancer driven by β-catenin signaling.Significance: Apatinib combined with oxaliplatin reprograms the tumor immune microenvironment in desert-type gastric cancer, enhancing the efficacy of immune checkpoint blockade and paving the way for optimized combination immunotherapeutic strategies.
