PROJECT SUMMARY/ABSTRACT Research: Cancer is the second leading cause of mortality in the world, with estimates as high as 1.9 million new diagnoses and 0.6 million deaths in the United States last year. Trillions of normally beneficial microbes, termed the microbiota, continuously colonize the mammalian intestine and emerging evidence indicates key roles for these microbes in impacting cancer. This includes both promoting tumor growth and progression, but also in supporting response to immunotherapies, raising the exciting possibility to manipulate microbiota to combat cancer, however the mechanisms by which microbiota influence cancer progression and immunotherapies remain poorly understood. Based on my published and new preliminary data, I hypothesize that host-microbiota interactions (i) promote tumor growth by limiting metabolites that provoke anti-tumor immunity, and (ii) shape systemic anti-tumor immunity and the outcome of immunotherapy by antigen-specific responses to gut microbiota via crosstalk of RORgt+ lymphocytes. These studies will define two novel pathways by which microbiota interacts with mammalian hosts to impact tumor growth, progression, and immunotherapy response, thus provoking novel opportunities for intervention. Career goals: My overarching goal is to become an independent investigator at an academic institution where I investigate the mechanisms by which host-microbe interactions modulate anti-tumor immunity and immunotherapy response for the treatment of cancer. Further, I aspire to become an inspirational and productive mentor as these are essential aspects of being an independent investigator. Career Development Plan: To become a successful independent investigator, I will further develop a various research, professional, and personal skills. These will include further acquiring expertise in cancer biology and microbiology techniques, as well as fostering collaborations and developing skills in writing, communicating, teaching, mentoring and laboratory management. My host laboratory and Weill Cornell Medicine provide an outstanding academic environment where trainees can fulfil these criteria by fostering scientific collaboration and enrolling in courses to develop skills in specialist scientific areas, personal development, and laboratory management. The mentorship I will receive will be of the highest standard. Further, in addition to my mentor and co-mentor, I have support from a team of independent investigators with extensive expertise in areas that will greatly facilitate the completion of experiments proposed and my career transition into independence. Career Development Environment: I will perform the K99 phase in the laboratory of Dr. Gregory Sonnenberg at Weill Cornell Medicine, which provides an outstanding environment in terms of the resources and facilities available. Weill Cornell Medicine is an ideal environment to develop during the K99 phase as I progress to become a successful independent investigator. The laboratory has access to all the instruments and facilities necessary to complete the experiments proposed in this application.

PROJECT NARRATIVE Cancer is the second leading mortality in the world, while many different treatments exist including revolutionary immunotherapies, adverse events are frequent and response rates are limited. Basic, translational, and clinical studies defined a key role for the gut microbiota in affecting tumor progression and immunotherapy efficacy, but the underlying mechanism remains at early stage of investigation. The focus of this proposal is to delineate two novel pathways by which microbiota interacts with mammalian hosts to impact tumor growth, progression, or immunotherapy response, thus provoking novel opportunities for intervention.