Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial

Carolina Alves Costa Silva (1, 2) , Gianmarco Piccinno (3) , Déborah Suissa (1, 2) , Mélanie Bourgin (2, 4) , Gerty Schreibelt (5) , Sylvère Durand (2, 4) , Roxanne Birebent (1, 2) , Marine Fidelle (1, 2) , Cissé Sow (1, 2) , Fanny Aprahamian (4, 2) , Paolo Manghi (3) , Michal Punčochář (3) , Francesco Asnicar (3) , Federica Pinto (3) , Federica Armanini (3) , Safae Terrisse (6) , Bertrand Routy (7, 8) , Damien Drubay (2, 9) , Alexander M M Eggermont (10, 11, 12) , Guido Kroemer (13, 2, 14, 15) , Nicola Segata (3, 16) , Laurence Zitvogel (1, 2, 17) , Lisa Derosa (1, 2) , Kalijn F Bol (5) , I. Jolanda M. de Vries (5)

1 ITIC - Immunologie anti-tumorale et immunothérapie des cancers
2 IGR - Institut Gustave Roussy
3 UNITN - Università degli Studi di Trento = University of Trento
4 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
5 Radboud University Medical Center [Nijmegen]
6 AP-HP - Hopital Saint-Louis [AP-HP]
7 CR CHUM - Centre de Recherche du Centre Hospitalier de l’Université de Montréal
8 CHUM - Centre Hospitalier de l'Université de Montréal
9 U1018 (Équipe 2) - Oncostat
10 UMCU - University Medical Center [Utrecht]
11 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
12 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
13 CRC - UMR_S 1138 - Métabolisme, Cancer et Immunité
14 SIRIC CARPEM - Cancer Research and Personalized Medicine - CARPEM [Paris]
15 HEGP - Hôpital Européen Georges Pompidou [APHP]
16 ESMO - European Institute of Oncology [Milan]
17 CIC 1428 , CBT 507 - Centre d'Investigation Clinique en Biotherapie des cancers

Abstract Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune tonus, earned its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years ( p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii , and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions.

Domaines: Sciences du Vivant [q-bio]

Carolina Alves Costa Silva, Gianmarco Piccinno, Déborah Suissa, Mélanie Bourgin, Gerty Schreibelt, et al.. Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial. Nature Communications, 2024, 15 (1), pp.1633. ⟨10.1038/s41467-024-45357-1⟩. ⟨hal-04596722⟩