Abstract 1042: Clinical and immune correlates of response to neoadjuvant chemoimmunotherapy in dMMR/MSI-H gastric cancer

Abstract Background: Neoadjuvant chemoimmunotherapy (NCIT) has shown promising efficacy in resectable deficient DNA mismatch repair/microsatellite instability-high (dMMR/MSI-H) gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC), yet predictive biomarkers of response remain unclear. Methods: We analyzed 22 patients with resectable dMMR/MSI-H GAC/GEJAC treated with perioperative sintilimab plus oxaliplatin and S-1 (SOX). Clinical response, pathological regression, genomic alterations, and tumor microenvironment (TME) features were characterized by imaging, histopathology, multi-omics profiling, and multiplex immunohistochemistry. Patients were classified as responders or non-responders based on radiological and pathological evaluations. Results: Radiological partial response was achieved in 10 of 22 patients (45.5%). Seventeen underwent R0 resection, with Becker tumor regression grades 1a, 1b, and 2 in 10, 1, and 6 cases, yielding a pathological complete response rate of 58.8%. Two-year event-free and overall survival were 81.8% and 80.7%. Non-responders exhibited poorer survival and greater baseline intratumor heterogeneity, with enriched mutations in NF1, KDR, CDKN2A, and PLK1. Transcriptomic profiling revealed upregulation of GYLTL1B, PHLDA1, IGFN1, and SH2D5 in responders, alongside activation of proliferative (E2F, MYC targets) and immune-stimulatory (TNFA-NFKB, interferon) pathways. In contrast, non-responders lacked these signatures and showed immunosuppressive TME features, including elevated methylated tumor-infiltrating lymphocytes, Th17 signature expression, and M1 macrophage infiltration. Post-treatment analysis indicated favorable immune remodeling in responders, marked by increased dendritic and NK cells and decreased M1 macrophages, while non-responders maintained an M1-dominant state. Predictive biomarkers such as CDKN2A mutation, Fanconi anemia pathway alteration, and specific transcriptomic signatures correlated with both response and prognosis. Conclusions: NCIT yielded high pathological response and survival rates in dMMR/MSI-H GAC/GEJAC. Integrated molecular and immune profiling identified genomic and transcriptomic determinants of response, supporting biomarker-guided therapeutic strategies in this molecularly defined cohort. Citation Format: Pengfei Yu, Xingmao Huang, Xiangliu Chen, Hang Chen, Song Wang, Di Wang, Junrong Yan, Jiahui Chen, Qing Wei, Zequan Wu, Shengxin Fang, Han Chen, Hongtao Wang, Chengkang Zhu, Ling Huang, Yian Du, Hua Bao, Haimeng Tang, Xue Wu, Xiangdong Cheng. Clinical and immune correlates of response to neoadjuvant chemoimmunotherapy in dMMR/MSI-H gastric cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1042.