Abstract 6743: Peripheral immune profiling from the DIET trial - A randomized double blinded dietary intervention study in melanoma patients receiving immunotherapy

Abstract Background: Dietary fiber intake is associated with improved response to immune checkpoint blockade (ICB) in melanoma. The phase II Diet and Immune Effects Trial (DIET, NCT04645680) was conducted in melanoma patients receiving ICB testing the effects of a high fiber diet intervention vs. healthy control diet. Our early results revealed that the high fiber diet intervention is feasible with promising improvements in treatment outcomes. Herein we report the secondary objective of the effects of dietary intervention on systemic immunity by arm. Methods: Patients were randomized (2:1) to either a high fiber diet (30-50 g/d ramped-up fiber) or healthy control diet (20 g/d fiber). Cryopreserved paired (pre vs post dietary interventions) peripheral blood mononuclear cells (PBMC) were collected longitudinally and used for NanoString gene expression profiling and CyTOF mass cytometry analyses. For translational human-to-mouse fecal microbiota transplant (FMT) studies, mice received patient stool collected either pre or post high fiber intervention, followed by melanoma inoculation and anti-PDL1 treatment. Endpoint peripheral leukocytes and spleen specimens were collected for CyTOF mass cytometry. Results: Using NanoString, we were able to identify decreased abundance scores of circulating macrophages (p=.018) and neutrophils (p=.035) (by cell type deconvolution) as well as classical monocytes (p=.06) and dendritic cells (p=.06) (Signature from Lam et al. Cell 2021) within week 5-8 of dietary intervention in high fiber (n=11) vs control arm (n=4). Pathway analysis showed higher transcriptional levels of T cell activation gene signature and T cell receptor signaling in the high fiber arm versus a higher level of Toll-like receptor signaling and type-1 interferon signaling in the control arm. These findings were validated at the protein level by CyTOF, which demonstrated reduced circulating classical monocytes (p=.0059) and increased frequency of effector-memory T cells (p=.01 in CD8+, p=.032 in CD4+) in the high fiber vs control arm within week 5-8 of dietary intervention. Within the high fiber arm, these findings were more prominent in those receiving combination nivolumab + ipilimumab (n=3) compared to those receiving pembrolizumab or nivolumab monotherapy (n=7). Human-to-mouse FMT studies also revealed an improved ICB response with lower frequency of monocytes and dendritic cells in post-high fiber diet stool recipients in the circulation and spleens. Conclusion: Our analyses suggested microbiome-dependent benefits of a high fiber diet in reducing circulating monocytes and potentially enhancing T cell activation in the peripheral blood. Circulating monocyte levels are known to negatively correlate with ICB response, warranting further mechanistic study on dietary fiber mediated regulation of peripheral immunity during immunotherapy. Citation Format: Yufan Qiu, Yan Jiang, Nazli Dizman, Courtney Nicholas, Yuwei Zhang, Sreyashi Basu, Elizabeth Burton, Michael A. Davies, Nadim J. Ajami, Padmanee Sharma, Jennifer A. Wargo, Jennifer L. McQuade, Carrie R. Daniel, . Peripheral immune profiling from the DIET trial - A randomized double blinded dietary intervention study in melanoma patients receiving immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6743.