Identifying the mechanism of anti-colorectal immunity induced by mucoinvasive colonic bacteria

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Abstract Colorectal cancer (CRC) is a leading cause of cancer-related death and its incidence is on the rise in young people. Colorectal tumors are often detected at late stages where therapy often fails. Immunotherapy is revolutionizing the treatment of many types of cancer but is only effective for a very small subset of CRC patients. Thus, there is a critical need for improved therapies for CRC. Colorectal tumors grow from the intestinal epithelium and interact with the colonic microbiota. CRC has been associated with shifts in the composition of the microbiota that promote inflammation and tumor growth. The microbiota can also shape colonic T and B cell immune responses and is a critical modulator of the efficacy of tumor immunotherapy. Using a mouse model of CRC (AOM/DSS) we show that colonization with a single bacterial taxon: Helicobacter hepaticus, after tumors have already developed, leads to a reduction in tumor burden and size. H. hepaticus also increased the number, size and organization of Tertiary lymphoid structures (TLS) next to colorectal tumors. The presence of TLS is associated with positive outcomes in CRC patients, but how they act to increase anti-tumor immunity is not known. H. hepaticus-dependent tumor reduction depended upon CD4 T cells and B cells but not CD8 T cells. Most H. hepaticus-specific CD4+ T cells differentiated into T Follicular Helper (TFH) cells and localized in TLS. Importantly, CD4cre Bcl6flox mice, that cannot form TFH cells, also failed to either form TLS or control CRC growth, but transfer of H. hepaticus-specific CD4+ T cells completely restored the anti-tumor response. Our hypothesis is that the distinct mucus colonization properties of Hhep leads to activation of anti-Hhep TFH that interact with B cells to induce peri-tumoral TLS formation. Colonic TLS then act as platforms for the activation of anti-tumor CD4+ T cells, NK cells and B cells which invade the tumor to support effective anti-tumor immunity. We will test this hypothesis in two aims. First, we will identify the genes and behavior, (such as mucus/epithelial colonization) associated with Helicobacter-associated control over CRC. Next we will correlate the presence of TLS, TFH and B cells in human CRC patients with specific mucus and tumor resident bacteria. Finally, we will use our mouse models to identify whether TLS serve as platforms for more effective activation of anti-tumor T and B cells. Together, our proposal has the potential to identify the key bacterial components that should be targeted to augment anti-tumor immunity and colonic TLS. Further we may identify mechanisms by which TLS support anti- tumor immune responses which could be used to formulate therapeutic anti-CRC approaches. If successful we could identify mechanisms to rationally modify the microbiome to increase anti-tumor immunity.