Combining Apatinib and Oxaliplatin Remodels the Immunosuppressive Tumor Microenvironment and Sensitizes Desert-Type Gastric Cancer to Immunotherapy

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 (GC) due to intrinsic tumor heterogeneity and a highly immunosuppressive tumor microenvironment (TME). Transforming tumors from immunosuppressive to immunostimulatory is a potential approach to enhance ICB response. Here, we developed a chromosomal instability (CIN) subtype GC mouse model with an immunoactive TME and a stem cell-originated mouse-derived allograft (MDA) 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 MDA tumors. The tyrosine kinase inhibitor apatinib reprogrammed the TME by increasing CD8+ T cells and IGHA+ plasma cells 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 GC. Collectively, these findings identify potential drug targets for immune desert-type GC driven by β-catenin signaling.