Abstract IA03: Control over colorectal tumor growth via bacteria-specific T-cell activation of the local immune response

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related death and its incidence is on the rise, particularly in young people. Therapy for late-stage CRC is often ineffective, and colorectal tumors are most often detected at stage 3 or 4. 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 tremendous need for improved therapies for CRC. Colorectal tumors grow from the intestinal epithelium and are therefore subject to interaction with the dense and diverse colonic microbiota. Indeed, CRC has been associated with shifts in the composition of the microbiota that effect inflammation and tumor growth. How the microbiota shapes the CRC immune microenvironment is not fully understood. In general, the microbiota can directly shape T-cell responses, directing the differentiation of CD4 T cells to develop into either regulatory (Treg) or effector (Th1, Th17, etc.) T cells. This is particularly true of those T cells local to the intestine that are often specific to antigens derived from intestinal bacteria. We became interested in how colonization with different bacterial taxa might affect the T-cell immune response and control over colorectal cancer. Using a mouse model of CRC, we show that colonization with a single bacterial taxon, after tumors have already developed, leads to a reduction in tumor burden and size. Bacteria-dependent tumor reduction depended upon CD4 T cells but not CD8 T cells as antibody depletion of CD4 T cells completely abrogated the effect. Accordingly, de novo bacterial colonization was associated with a colorectal tumor environment that possessed fewer Tregs, increased CD4 IFNgamma-producing T cells, and increased CD103+ dendritic cells. We also observed that colonized mice develop increased numbers of organized tertiary lymphoid structures that were adjacent to colonic tumor. Importantly, bacteria-specific CD4 T cells were commonly found in these tertiary lymphoid structures, as were bacteria. Our hypothesis is that microbiota-driven and T cell-dependent development of TLS structures leads to enhanced tumor antigen presentation and augmented antitumor immune responses. This work has the potential to inform CRC therapies via the rational modification of the local microbiota to support TLS formation and antitumor immunity. Citation Format: Abigail Overacre-Delgoffe, Hannah Bumgarner, Tim Hand. Control over colorectal tumor growth via bacteria-specific T-cell activation of the local immune response [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA03.