Identifying gut bacterial molecules and mechanisms that promote an anti-tumor response to immunotherapy - Project Summary The immune system is capable of mounting a robust anti-cancer response. However, cancer cells can disrupt this immune response, hijacking immune checkpoint mechanisms which act as brakes on the endogenous anti-cancer response. Antibodies that block immune checkpoints (e.g., a-PD-L1, a-PD-1, and a- CTLA4) have revolutionized cancer treatments, yet, only a fraction of patients respond. Understanding the underlying mechanisms that promote a durable anti-tumor response to checkpoint blockade therapy is crucial to develop effective therapeutics that can treat a wider range of cancer patients. The gut microbiota is a key variable in the anti-tumor response to immunotherapy, even for tumors outside of the intestine. The goal of this project is to identify gut bacterial molecules that promote an anti-tumor response to PD-1 blockade and their mechanisms of action. I hypothesize that certain gut bacterial surface components prime immune cells and these bacterial-immune interactions within the gut are essential for the anti-tumor immune response to PD-1 blockade at extra-intestinal sites. I propose to test this hypothesis by determining the key immune components of the microbe-dependent immune response in the tumor (Aim 1), the key bacterial molecules which promote the anti-tumor response (Aim 2), and the mechanisms by which microbes and immune cells interact within the gut (Aim 3). These studies are significant because by identifying active, anti-tumor gut bacterial molecules and mechanisms, more effective therapeutics can be developed that will broaden the range of patients who respond to checkpoint therapy. My long-term goal is to run a research group that investigates the interactions between gut bacteria and the immune system. My motivation is to identify new bacterial molecules and their mechanisms of action that can be harnessed in the clinic as therapeutics for cancer and other diseases. I trained in Dennis Kasper’s lab gaining expertise in gnotobiotic mouse work, microbiota analysis and culture, click chemistry, and bacterial molecule separation leading to the preliminary data for Aims 1-3. To learn about the immune response to PD-1 blockade and co-signaling molecules, I collaborated with Arlene Sharpe’s lab and obtained preliminary data for Aims 1-3. This collaboration has led to two patent applications and discussions with industry for drug translation. To understand how bacteria directly interact with gut cells, I developed a mouse microfluidic gut chip in a collaboration with Donald Ingber’s lab at the Wyss institute at Harvard that I plan to use in Aims 2 and 3. By taking advantage of the excellent work environment at Harvard Medical School, I have acquired a unique skill set stemming from experience with both the academic research environment and with industry discussions for clinical translation. This training enables me to run my own research group that will investigate gut bacterial/immune interactions that can be employed to create novel therapeutics.
