CEACAM5/6+ cancer cell and IL1B+ macrophage-mediated resistance in anti-PD-1 treated gastric cancer
Presenter: Liudeng Zhang, BS Session: Immune Response to Therapies Time: 4/22/2026 9:00:00 AM → 4/22/2026 12:00:00 PM
Authors
Liudeng Zhang 1 , Jian Chen 2 , Yikai Luo 1 , Lie Wang 2 , Han Liang 1 1 Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, 2 Zhejiang University, Hangzhou, China
Abstract
Immune checkpoint blockade therapy has shown limited efficacy in gastric cancer, with most patients developing resistance through mechanisms that remain incompletely defined. Here, we generate a comprehensive single-cell RNA sequencing atlas of 526,583 cells from gastric cancer patients treated with anti-PD-1 plus chemotherapy, analyzing paired pre- and post-treatment samples to capture dynamic resistance mechanisms. We identify two distinct resistance pathways that emerge during treatment. First, CEACAM5/6+ cancer cells are markedly enriched in pre-treatment non-responders and predict treatment failure. These CEACAM5/6+ epithelial cells show the highest tumor scores and correlate with increased regulatory T cell infiltration expressing CEACAM1, establishing an alternative checkpoint axis that bypasses PD-1/PD-L1 blockade. External validation in independent cohorts confirms CEACAM5/6 expression as a robust predictor of anti-PD-1 resistance. Second, we uncover a macrophage-driven inflammatory cascade central to treatment resistance. IL-1β+ macrophages serve as the primary source of NF-κB pathway activation across the tumor microenvironment, triggering downstream IL-6 production, Th17 cell differentiation, chronic inflammation and epithelial-mesenchymal transition. This macrophage module is significantly enriched in post-treatment non-responders, with TNF-high expressing monocyte-macrophages absent in responders but prevalent in resistant tumors. The resulting inflammatory milieu drives PD-L1 upregulation across multiple cell types, creating a self-reinforcing immunosuppressive niche. Collectively, these findings nominate CEACAM5/6⁺ epithelial cells and IL-1β⁺ inflammatory macrophages as actionable therapeutic targets for overcoming anti-PD-1 resistance in gastric cancer, providing a mechanistic framework and rational blueprint for next-generation combination immunotherapy strategies.
Disclosure
L. Zhang, None.. J. Chen, None.. Y. Luo, None.. L. Wang, None.. H. Liang, None.
Cited in
Control: 1439 · Presentation Id: 9529 · Meeting 21436