<b>Computational model of intestine microbiome influence on melanoma immunotherapy outcome</b>

Immunotherapy has proven to be a boon for patients grappling with metastatic melanoma, significantly enhancing their clinical condition and overall quality of life. A compelling connection was discovered between the composition of the intestinal microbiome and the effectiveness of immunotherapy substantiated in both animal models and human patients. Nonetheless, the precise biological mechanisms through which gut microbes influence melanoma treatment outcomes remain poorly understood. Utilizing a robust dataset of 680 stool metagenomes encompassing various treatment outcomes from melanoma patients, we constructed a detailed catalog of Metagenome-Assembled Genomes (MAGs) to delve into the microbiome's compositional and functional attributes. Our study unearthed significant findings that deepen the understanding of the intricate link between the intestinal microbiome and melanoma immunotherapy effectiveness. Specifically, we discovered the specific bacterial profile in patients with favorable treatment outcomes, characterized by a prevalence of microbial MAGs proficient in polysaccharide utilization, along with those responsible for cobalamin, amino acids, and fatty acids production. Conversely, patients with unfavorable outcomes showed a prevalence of microbial autotrophy in these crucial substances. Furthermore, our investigation into the short-chain fatty acids biosynthesis pathways, known for their immunomodulatory roles, unveiled a differential abundance of these pathways among the specific MAGs. Among other things, the cobalamin-dependent Wood-Ljungdahl pathway of acetate synthesis was directly associated with immunotherapy effectiveness. Our findings advanced understanding of biological mechanisms of gut microbiome influence on melanoma immunotherapy outcome and provided a foundation for further investigations aimed at enhancing immunotherapy effectiveness through microbiome modulation. Stool metagenomes from seven published studies were used for obtained of metagenome-assembled genome catalog [Frankel et al., 2017; Gopalakrishnan et al., 2018; Matson et al., 2018; Baruch et al., 2021; Davar et al., 2021; Spencer et al., 2021; Lee et al., 2022]. References: 1) Frankel, Arthur E., et al. "Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients." Neoplasia 19.10 (2017): 848-855. doi: 10.1016/j.neo.2017.08.004. 2) Gopalakrishnan, Vancheswaran, et al. "Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients." Science 359.6371 (2018): 97-103. doi: 10.1126/science.aan4236. 3) Matson, Vyara, et al. "The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients." Science 359.6371 (2018): 104-108. doi: 10.1126/science.aao3290. 4) Baruch, Erez N., et al. "Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients." Science 371.6529 (2021): 602-609. doi: 10.1126/science.abb5920. 5) Davar, Diwakar, et al. "Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients." Science 371.6529 (2021): 595-602. doi: 10.1126/science.abf3363. 6) Lee, Karla A., et al. "Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma." Nature Medicine 28.3 (2022): 535-544. doi: 10.1038/s41591-022-01695-5. 7) Spencer, Christine N., et al. "Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response." Science 374.6575 (2021): 1632-1640. doi: 10.1126/science.aaz7015.