DELINEATING GUT-MEDIATED RESPONSE AMONG MELANOMA PATIENTS UNDERGOING ANTI-PD1 IMMUNOTHERAPY

The advent of immune checkpoint inhibition therapy markedly improved outcome for melanoma. However, response remains heterogeneous, with about half of the patients being refractory or developing relapse. Meanwhile, current knowledge on the causal link between the gut microbiota and immunotherapy response is limited to cross-sectional analyses. In this study, we perform a longitudinal study of melanoma patients undergoing immunotherapy to delineate gut changes related to response and identify gut and host factors involved. To study response-related gut microbiota changes during ICI, patients with unresectable melanoma (n=23) from two Italian hospitals were followed at baseline and over the course of anti-PD1 immunotherapy, collecting fecal and blood samples, from which we surveyed the gut microbiota, metagenome, and systemic immune profile. For validation, fecal samples from tumor-free subjects were used as reference; gut variability measures were compared against publicly available longitudinal studies; finally, multi-cohort validation was carried out on metagenomic data from baseline melanoma patients across nine studies. Our results demonstrate that the gut microbiota is distinctly stable among complete responders (CR), especially at later cycles of therapy. We identify and validate a core of longitudinally stable gut microbiota taxa in CR, comprising mostly Clostridia taxa, which also associate with markers for stability and positive systemic state. At the gut functional level, our data demonstrate a key role for Lachnospiraceae-carried flagellin genes in driving a productive anti-tumor response. Overall, we propose microbiota stability during ICI therapy as a consequential feature of an immune-beneficial Clostridia-rich gut, resulting in good response to immunotherapy.