Elucidating the role of intratumoral microbiota on immunotherapy efficacy - PROJECT SUMMARY/ABSTRACT Microbes live in primary tumors across organ systems and in tumor metastases, making the microbes an intrinsic and essential component of the tumor microenvironment, yet what types of microbes reside in tumors and how they contribute to the tumor microenvironment, T cell function, and immunotherapy response are unknown. We modeled estimated tumor bacterial burden against the known objective response rate to immunotherapy across tumor types and observed a remarkable correlation between high bacterial burden and high response rates to immunotherapy, suggesting that the community of microbes in the tumor, or tumor microbiota, plays a pivotal role in influencing the response rate to immunotherapy. Our preliminary data supports this hypothesis, showing that increased numbers of microbial species in tumor microbiota correlate with increased numbers of immune cells in the tumor and response to immunotherapy in head and neck squamous cell carcinoma patients. However, the microbial composition of and the mechanisms by which intratumoral microbiota influence these clinical outcomes are currently unknown. While intratumoral microbiota communities remain a mystery, recent studies have implicated the influence of intestinal microbiota on immunotherapy outcome, whereby responding patients harbor specific intestinal microbial communities associated with enhanced systemic immunity and intratumoral immune infiltration. Interestingly, microbes from the gastrointestinal tract traffic to distant tumors, thus potentially seeding the intratumoral microbiota. For example, Bifidobacteria, a bacterial genera associated with immunotherapy efficacy, is known to translocate from the intestine to distant tumors. Thus, intestinal microbiota may influence immunotherapy response through microbial dissemination to tumors. Herein we propose to test whether intestinal microbes associated with immunotherapy efficacy promote bacterial or bacterial product translocation from the intestine to the lymph nodes and/or tumor. Further, we aim to uncover unique mechanisms by which intratumoral microbiota, through either direct immune cell interaction or the modulation of tumor microenvironment, influence immunotherapy efficacy. This knowledge may uncover unique opportunities to develop new therapeutic options for patients with cancer, either before standard of care treatments or synergistically through augmentation of current immunotherapy regimens. Toward this end, we hope to leverage the knowledge we gain from this proposal with respect to intratumoral microbiota to develop bacterial drugs in the localized, intratumoral setting thus minimizing systemic effects of potentially detrimental disruptions to intestinal microbial communities. Thus, our mechanistic approach has the potential to lead to innovative microbiome-based treatments that may increase the number of patients responding to immunotherapy.
