Abstract 2220: Gut microbiome impacts the tumor microenvironment and enhances the effectiveness of anti-PD1 therapy in head and neck cancer

Abstract Although the Food and Drug Administration has approved anti-PD1 as an effective therapy for recurrent head-and-neck squamous cell carcinoma (HNSCC), its response rate remains limited to approximately 10-30%, and the prognosis for patients is still poor. In this study, we seek to enhance the therapeutic efficacy of anti-PD1 for recurrent HNSCC. First, we compared the pathology of responders and non-responders to pembrolizumab treatment for HNSCC. Immunohistochemical staining revealed a significantly higher abundance of CD8 T cells in responders, and RNA sequencing, through Gene Set Enrichment Analysis (GSEA), demonstrated a significant activation of CD8 T cell pathways in responders compared to non-responders. Second, 16S full-length sequencing of stool DNA identified an enrichment of Eggerthella lenta (E. lenta) in responders. Furthermore, the presence of E. lenta was positively correlated with CD8 T cell activation and cytotoxic activity. Third, to assess the impact of E. lenta on the anti-tumor response to anti-PD1 therapy in vivo, we implanted HNSCC tumors subcutaneously in antibiotic-induced microbiome depletion mice. The mice were treated with anti-PD1 monoclonal antibody and oral E. lenta administration, resulting in significant tumor regression compared to that of the controls (no treatment), anti-PD1 alone, or E. lenta alone. The excised xenograft HNSCC tumors were analyzed by flow cytometry, revealing that the combination of anti-PD1 therapy and oral E. lenta synergistically increased tumor-infiltrating CD8 T cells and enhanced their activation, as evidenced by elevated interferon-gamma and TNF-alpha expression. Metabolomic analysis identified changes in fatty acid pathways linked to CD8 T cell activation, E. lenta administration, and responders. Our results suggest that E. lenta enhances the response to anti-PD1 therapy, offering new insights into the connection between the microbiome and cancer immunotherapy. Citation Format: Po-Han Lin, 1 Ya-Hui Chen, 1 Chi-Maw Lin, 1 Jessica Tien Yu Ho, 2 Chih-Hao Yu, 1 Chen-Yi Wang, 1 Yuan-Chia Chu, 1 Chun-Yu Liu, 3 Ying-Cheng Chiang, 1 Ruey-Long Hong1. Gut microbiome impacts the tumor microenvironment and enhances the effectiveness of anti-PD1 therapy in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2220.