Delineating Strategies to Enhance Immunotherapy Response via Microbial Targeting of Tertiary Lymphoid Structures

The body’s immune system has a tremendous ability to fight disease including cancer, with strategies to reinvigorate immune responses against cancer winning the Nobel Prize in 2018 – and multiple immunotherapy drugs approved for the treatment of cancer. Despite this, most patients who are treated with immunotherapy are not cured, and there is an urgent need to develop novel strategies to improve outcomes to treatment with immunotherapy. Our group has focused on this for over a decade, and we have identified novel predictors of response to immunotherapy that can be targeted, including immune cells and aggregates within the cancer itself, as well as microbes (bacteria, viruses, and fungi) within the gut. However, the interplay between immune cells in the cancer and microbes in the gut is incompletely understood. This has been an intense area of investigation in our group over the last several years, and we now have evidence that specific microbes in the gut of patients may induce immune cell aggregates and immunotherapy responses across several cancer types. This opens up therapeutic opportunities to target gut microbes to improve outcomes to treatment with immunotherapy for cancer, however critical information is still needed. Through this proposal, we will identify gut- and tumor- associated microbes that are associated with enhanced immune aggregates in tumors and immunotherapy response in patients with several different cancer types. Additionally, we will identify antibodies that recognize (or are stimulated by) microbes that could be manufactured and administered to patients to improve patient outcomes. Finally, we will test strategies targeting microbes and antibodies to improve anti-tumor immunity and immunotherapy response in well-established models. Taken together, our work will identify therapeutic strategies targeting microbes and antibodies to improve cancer outcomes, with the potential to inform studies to intercept and prevent cancer in future studies.