Abstract 2377: Gut microbiome modulation by a black raspberry nectar for improving anti-PD1 therapy effectiveness in pre-clinical cancer models

Abstract Immune checkpoint inhibitors (ICIs) have improved cancer survival rates, but only a small percentage of patients experience significant and sustained tumor responses. Recent evidence points to the gut microbiome as a modifiable factor that may improve the efficacy of ICIs. This study utilized a human clinical trial and an experimental model to assess whether a dietary intervention could enhance ICI therapeutic outcomes. Specifically, we investigated the effects of black raspberry nectar (BRB) consumption on the microbiome and subsequently in murine models of anti-PD1 cancer therapy. The BEWELL clinical trial was a randomized, placebo-controlled, cross-over dietary intervention trial where 40 individuals received 80 mL of BRB for 4 weeks or placebo for 4 weeks. The BRB altered the participants’ microbiomes, significantly enriching microbes in the family Lachnospiraceae. Mice were gavaged with microbiomes from human participants who exhibited significant Lachnospiraceae enrichment post-BRB dietary intervention showed substantial reductions in tumor volume following anti-PD1 therapy. These results suggest that Lachnospiraceae may be key in enhancing ICI response. To further isolate the impact of specific microbes, we focused on Blautia, a representative Lachnospiraceae genus, to determine whether its presence could individually improve ICI therapeutic outcomes. Mice gavaged with Blautia-enriched microbiomes and provided anti-PD1 therapy demonstrated significantly lower tumor growth rates (p-value = 0.012) and a higher frequency of tumor-free status than controls (78% vs60%). A metabolomic analysis revealed distinct metabolic changes, with L-carnitine levels elevated in mice showing smaller tumors (p-value = 0.013). No significant changes were observed in butyrate, indole-derivatives, or inosine, which were previously shown to alter ICI response, suggesting a novel mechanism. Our findings underscore the potential of Lachnospiraceae, particularly Blautia, in improving cancer treatment outcomes. By extending human dietary modifications into preclinical models, this study reveals a promising strategy for using microbiome composition as a tool to enhance ICIefficacy. Citation Format: Shiva Jahanbakhshi, Amna Bibi, Rebecca Hoyd, Caroline Dravillas, Nyelia Williams, Shiqi Zhang, Aaditya Pallerla, Shankar Suman, Joseph Amann, Mounika Goruganthu, Tamio Okimoto, Yangyang Liu, Marisa A. Bittoni, Ni Shi, 2 Bailey Conrad, Lane Nevers, Kristen Heitman, Maxine Webb, Elizabeth M. Grainger, Madison Grogan, Christian Quiles, Tong Chen, Carolyn Presley, Lang Li, Patrick Bradley, Yael Vodovotz, David P. Carbone, Steve K. Clinton, Jiangjiang Zhu, Daniel Spakowicz. Gut microbiome modulation by a black raspberry nectar for improving anti-PD1 therapy effectiveness in pre-clinical cancer models [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 2377.