Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.07.242040v1?rss=1 Authors: Borgerding, J. N., Shang, J., Britton, G. J., Salmon, H., Bigenwald, C., Maier, B., Rose, S. R., Mogno, I. J., Kamphorst, A. O., Merad, M., Faith, J. J. Abstract: Recent studies demonstrate that gut microbiota regulate tumor response to immune checkpoint blockade. Still, the mechanisms by which microbiota control tumor response to immunotherapy remain unclear. We colonized germ-free mice with cultured human-derived microbiota prior to tumor inoculation. While no human donor microbiota altered tumor growth, two distinct gut microbiota inhibited tumor response to anti-PD-L1. Colonization with non-responder microbiota led to reduced tumor immune cell infiltration and modified antigen presenting cell phenotype. RNA sequencing of tumor-infiltrating CD8+ T cells revealed enrichment for stem cell-like genes in non-responders and reduced effector-like expression conferring cytotoxic potential. Antibiotic depletion and microbiota transplant restored anti-PD-L1 response in non-responders, with expansion of effector cells and cytotoxicity. Concomitant blockade of TNF similarly improved response to anti-PD-L1 and increased cytotoxicity. These results demonstrate inhibitory roles for the microbiota in checkpoint blockade and reveal the potential for microbiota transplant and TNF blockade to overcome microbiota-mediated resistance. Copy rights belong to original authors. Visit the link for more info