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 and CD8 IFNg-producing T cells and increased CD103+ dendritic cells (DCs). Based upon this preliminary data, our hypothesis is that colonization with this unique strain of bacteria directly affects the local the local tumor environment and colonic immune response, increasing CD4 T cell and CD103+ DC activation to drive stronger anti-tumor immune responses. Here we propose to explore the mechanism behind this effect in two aims. The first will look at whether bacteria are adhering or invading colorectal tumors and also whether the colonizing bacteria alone is sufficient to control colorectal tumor burden or whether it requires other members of the microbiota. The second will examine the specific role of bacteria-specific CD4 T cells and CD103+ DCs in mediating tumor control. At the conclusion of these studies we hope to have defined the role of microbiota- specific T cells in anti-tumor immune responses and made progress towards future efforts to augment tumor immunotherapy by modifying the intestinal microbiome.
Colorectal cancer is the third most common type of cancer and unfortunately, treatment for advanced disease is often ineffective. Colorectal cancer develops directly opposite the largest and most dense microbiome in the body and is shaped by local bacterial populatons. In this application we will test whether we can use a common bacteria to increase immune-based protection against colorectal cancer.
