Lin Guang-Tan, Yan Cheng, Li Lu-Jie, Qiu Xiao-Wen, Zhao Yu-Xuan, Lin Ju-Li, Chen Yu-Jing, Feng Chuan, Chen Shao-Qiong, Xie Jian-Wei, Zheng Chao-Hui, Nomura Sachiyo, Huang Chang-Ming, Li Ping, Cao Long-Long
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
Cancer Res. 2025 Jun 2;85(11):2117-2133. doi: 10.1158/0008-5472.CAN-24-2697.
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.
在过去十年中，免疫检查点阻断（ICB）疗法在癌症治疗方面取得了重大突破。然而，由于内在的肿瘤异质性和高度免疫抑制的肿瘤微环境（TME），ICB在荒漠型胃癌中大多无效。将肿瘤从免疫抑制状态转变为免疫刺激状态是增强ICB反应的一种潜在方法。在本研究中，我们开发了一种具有免疫活性TME的染色体不稳定亚型胃癌小鼠模型和一种具有免疫抑制TME的干细胞起源的小鼠异种移植模型，以研究调节肿瘤免疫表型的机制，并揭示重塑TME的治疗策略。阻断β-连环蛋白信号通路可减弱小鼠异种移植肿瘤的免疫化疗耐药性。酪氨酸激酶抑制剂阿帕替尼通过增加CD8+T细胞和IGHA+浆细胞浸润以及减少M2巨噬细胞来重编程TME，但阿帕替尼也会诱导人和小鼠荒漠型肿瘤中PD-L1和CD80的表达。奥沙利铂降低了阿帕替尼诱导的免疫检查点表达，并增强了免疫治疗的抗肿瘤疗效。一项前瞻性临床试验（NCT04195828）表明，阿帕替尼联合ICB和化疗的新辅助方案对荒漠型胃癌患者有效。总体而言，这些发现确定了由β-连环蛋白信号驱动的免疫荒漠型胃癌的潜在药物靶点。意义：阿帕替尼联合奥沙利铂可重编程荒漠型胃癌的肿瘤免疫微环境，增强免疫检查点阻断的疗效，为优化联合免疫治疗策略铺平道路。
