Abstract 6680: High-fiber diet induces favorable gut microbiota, reduces immunosuppression, and inhibits lung cancer development

Abstract Emerging evidence suggests that resident microbial communities act as a central regulator of host homeostasis. The dynamic structure, composition, and function of gut microbiota can be influenced by numerous factors, among which nutritional profile act as most crucial determinant. Microbial consortia inhabiting the gut have been implicated in the etiology and pathogenesis of various cancers and are known to influence cancer immunosurveillance and response to immunotherapy. Despite these known associations, the underlying mechanisms by which dietary interventions such as those rich in fiber (high-fiber diet) regulate gut-immune axis in prevention of lung cancer are poorly defined. Here, we employed a human-relevant mouse model in which knockout of G-protein coupled receptor 5A (Gprc5a−/−) and exposure to tobacco lead to development of preneoplasia and lung adenocarcinoma (LUAD). Mice were randomly grouped based on dietary treatment: no fiber (control), 10% cellulose, 10% pectin-inulin following weaning (early life) or after transplant of MDA-F471 NNK-induced LUAD cells (dietary intervention). Tumor growth and volumes were most significantly reduced in mice fed a high-fiber pectin-inulin diet. Notably, anti-tumor effects of the high-fiber diet were observed in both early life and later dietary intervention settings. 16S rRNA-Seq analysis of fecal pellets revealed significant differences in gut alpha as well as beta diversity, the latter indicating clear separation of community structure between fiber-deprived versus high-fiber diet groups. Evidently, gut microbiota of pectin-inulin fed mice displayed significantly elevated relative abundance of Bacteroides sartorii, Bacteroides caecimuris, Akkermansia muciniphila and Bifidobacterium pseudolongum, taxa that have been reported to be strongly associated with favorable responses to immunotherapy. High-fiber fed mice also showed significantly reduced fractions of tumor-promoting genera such as Odoribacter and Alistipes. These effects were accompanied by widespread changes in the tumor immune microenvironment between fiber-rich and fiber-poor groups. Pectin-inulin fed mice displayed enhanced antitumor immune responses evident by remarkably increased fractions of B lineage cells, cDC1s and M1-likemacrophages and, conversely, reduced levels of activated cDC2s, M2 macrophages and polymorphonuclear myeloid-derived suppressor cells. Our findings inform on novel mechanisms by which dietary fiber robustly impacts gut consortia and immune milieu in the inhibition of LUAD. Our findings also suggest that the incorporation of dietary fiber in cancer treatment (e. g. , immunotherapy) could improve outcomes for patients with LUAD. Citation Format: Manvi Sharma, Yuejiang Liu, Hannah Moreno, Inti C. Reischle, Mohamed A. Jamal, Tieling Zhou, Zahraa Rahal, Chidera O. Chukwuocha, Ke Liang, Robert R. Jenq, Matthew C. Ross, Kristi L. Hoffman, Humam Kadara. High-fiber diet induces favorable gut microbiota, reduces immunosuppression, and inhibits lung cancer development 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 (6Suppl): Abstract nr 6680.