Diet-Microbe-Host Interaction Elicits Anti-Tumor Immune Response in Mouse Models of Colorectal Cancer

Immune checkpoint inhibitors (ICI) have transformed cancer treatment, yet response to ICI is not universal, especially for colorectal cancer (CRC). While certain gut microbiota members have been associated with ICI treatment response in patients, mechanisms governing microbial modulation of anti-tumor immunity remain elusive. Here we show that gut microbiome sulfur amino acid (Saa) metabolic gene abundance correlates with improved anti-tumor immunity and ICI response, prompting us to test the effects of dietary Saa in mouse models of CRC. A high Saa diet slowed tumor growth in a heterotopic CRC model, and augmented CD8+ T cell infiltration and decreased neoplastic progression in a genetically-driven CRC model. The high Saa diet increased the abundance of Mucispirillum schaedleri, which increased CD103+ conventional dendritic cells (cDC1) abundance and activation state in the tumor draining lymph nodes (TDLN), enhancing anti- tumor immune responses. Strikingly, M. schaedleri conditioned medium (CDM) induced XCL1 production by Natural Killer T (NKT) cells in vitro, pointing to a direct causal effect of M. schaedleri on this known cDC1 activation pathway. Thus, we have uncovered a diet-microbiota- host interaction and signature regulating anti-tumor immunity and provide a framework for identifying and preclinically evaluating microbiota-targeted, diet-based cancer adjunctive therapies.