Harnessing human gut-derived Bacteroides to drive systemic anti-tumor immunity - Although immune checkpoint blockade has transformed therapeutic options for lung cancer, its efficacy differs widely even between patients with remarkably similar disease, and while few have lifelong remissions, the majority relapse after several months. Numerous clinical studies and pre-clinical mouse models have demonstrated that certain compositions of mammalian gut microbiota (harboring particular bacteria) as well as certain largescale manipulations (such as fecal transplant) can provide dramatic anti-tumor immunity in tissues far removed from the intestine. As researchers heed this phenomenon, there are continued reports of various “efficacious” bacteria. However, the mechanism by which any one of these gut-restricted commensals is able to elicit an immune response in a distant tumor remains unknown. We do not appreciate in which anatomy the host immune system is first provoked by the microbiota—is it locally within the mucosa, within the tumor microenvironment itself, the draining lymph node, or elsewhere? We also do not know whether the microbiota directly re-program cytotoxic T cells, whether they indirectly improve antigen presentation, or whether any number of cells that participate upstream of the anti-tumor response are the first to be triggered. We have set up a reductionist model in our preliminary work to clarify this, wherein gut colonization with a commensal Bacteroides leads to striking anti-tumor responses in immunogenic lung tumor implants. The phenotype is T cell-dependent, and it is strong enough to persist even in the absence of exogenous immunotherapy. We also find a closely related but distinct Bacteroides species, which is capable of similarly colonizing the gut; however, it does not render any anti-tumor effect, and so it serves as a control comparator. Furthermore, bioengineering collaborators have established a “next-generation parabiosis” system, such that mice housed in separate cages can each have their vasculature cannulated, and microfluidics can continuously exchange blood flow. Remarkably, we find that a tumor-bearing mouse lacking gut colonization will exhibit anti-tumor efficacy once it exchanges blood with a colonized mouse. Therefore, we wish to ask: through which blood-borne component is efficacy transferred, and which host cell is first triggered? The applicant, Dr. Rabi Upadhyay, an Assistant Professor in the Department of Medicine and the Perlmutter Cancer Center at NYU Grossman School of Medicine, has outlined a 5-year career plan that builds on his scientific background in immunology and microbiology as well as his clinical training in medical oncology and immunotherapy. Dr. Upadhyay will conduct the proposed research under the mentorship of Dr. Dan Littman, an internationally recognized expert in T cell immunology with a strong track record of training successful physician scientists. Dr. Littman’s laboratory and NYU Perlmutter Cancer Center provides the ideal institutional environment for Dr. Upadhyay to embark on the proposed research program, and transition to a position as an independent academic investigator with his own laboratory and eventual R01 funding.
