Abstract 6200: Single-cell analyses unravel novel immune and tumor cell characteristics linked to the response to neoadjuvant immune checkpoint blockade in patients with gastric cancer

Abstract Background: Gastric cancer remains the leading cause of cancer-related deaths worldwide, ranking fifth for incidence and fourth for mortality. Combining neoadjuvant therapy with immune checkpoint inhibitors has demonstrated improved outcomes for patients with gastric cancer. However, responses exhibit heterogeneity, and the understanding of the mediators influencing therapy response is limited. Methods: In this study, we collected 80 blood and tumor samples from 22 gastric cancer patients treated with XELOX/SOX alone or its combination with Nivolumab (anti-PD-1). Paired single-cell RNA-, TCR-, and BCR-sequencing were performed on pre- and post-treatment samples to investigate the dynamics of immune and tumor cells during the development of response/resistance to therapy. Results: Our findings revealed that elevated levels of baseline CD4 and CD8+ tissue-resident memory T (TRM) cells, in activated and stressed states, are associated with a superior response to combined therapy, and treatment further amplifies this cell population in responsive patients. Tracking T cell receptor clones across pre-/post-treated blood and tumor samples disclosed that the expanded clonotypes of TRM cells are exclusively detected in tumors, and considerable preexisting clones contribute to the expansion of these T cell populations following treatment. The simultaneous presence of TRM, B, and dendritic cells in pre-treated tumors predicted a favorable response, and they concertedly expanded in tumors responsive to anti-PD-1 therapy. Conclusions: Our findings highlight the significance of TRM cells in effective responses to anti-PD-1 therapies and indicate that their cellular communication with B and dendritic cells play a pivotal role in shaping the antitumor immunity elicited by combination therapy. Together, this study illuminates vital immune cell subsets during immune checkpoint blockade treatment, provides biological insights into the mechanism of successful combination therapy, and unravels potential targets for improving treatment efficacy in gastric cancer. Citation Format: Enyu Dai, Jiang-Jiang Qin, Can Hu, Zhiyuan Xu, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Yunhe Liu, Guangsheng Pei, Jiahui Jiang, Fuduan Peng, Yuanyuan Zhang, Andre Luis Faustino, Jaffer A. Ajani, Linghua Wang, Xiangdong Cheng. Single-cell analyses unravel novel immune and tumor cell characteristics linked to the response to neoadjuvant immune checkpoint blockade in patients with gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6200.