STABILITY OF THE GUT MICROBIOTA DURING ANTI-PD1 IMMUNOTHERAPY DEFINES COMPLETE RESPONSE IN MELANOMA PATIENTS.

• DOI: 10.5281/zenodo.8013450
• Publication Date: 2023-06-14
• Authors: Angeli D.G. Macandog; Carlotta Catozzi; Amir Nabinejad; Mariaelena Capone; Gabriele Madonna; Ester Cassano; Federica Armanini; Giovanna M. Jodice; Francesca Montani; Maria Tagliamonte; Salvatore Pece; Pier F. Ferrucci; Massimo Barberis; Luigi Buonaguro; Nicola Segata; Emilia Cocorocchio; Paolo Antonio Asc...; Teresa Manzo; Luigi Nezi

Abstract The advent of immune checkpoint inhibition (ICI) therapy markedly improved the outcome of melanoma. However, responses remain heterogeneous with about half of patients being refractory or experiencing relapse to anti-PD1. A causal link between the gut microbiota and modulation of the anti-tumor response has been established, however current knowledge is limited to cross-sectional analyses. To study response-related gut microbiota changes during ICI, patients with unresectable melanoma from two Italian hospitals (total n=23) were followed at baseline and over the course of anti-PD1 immunotherapy to collect fecal and blood samples, from which we surveyed the gut microbiota, metagenome, and systemic immune profile. Our gut dynamic measures demonstrate that, while the overall structure of the gut microbiota during ICI therapy is variable, changes are less pronounced in patients identified as complete responders, especially at later cycles. Using Shotgun metagenomic data, we further identify and validate a set of longitudinally consistent (stable) taxa in the gut that associate with systemic blood markers, supporting their immunomodulatory potential. Mechanistically, our data suggest that the Clostridia-rich gut microbiota of complete responders supports a productive immune response through flagellin-dependent tumor antigen mimicry along with specific immunomodulating metabolic activities. Overall, we propose microbiota stability among complete responders during ICI therapy as a consequential feature of a T-cell-beneficial gut.