The implementation of checkpoint blockade immunotherapy is having a major impact on cancer outcomes. However, a sizable subset of patients still fails to benefit, and prior research has shown that inadequate baseline T cell infiltration into the tumor microenvironment is associated with lack of clinical response. These findings point to poor spontaneous T cell activation and recruitment as a general mechanism of resistance and motivate the search for mechanisms that regulate the degree of T cell infiltration into the tumor microenvironment. Our group has previously identified tumor- intrinsic oncogene pathways as key variables that contribute to poor T cell recruitment and therapeutic resistance. Host-intrinsic factors such as germline polymorphisms in immune regulatory genes can also influence the degree of T cell infiltration. But in addition, a major environmentally-influenced variable has recently emerged, which is the composition of the commensal microbiota. Recent work in our group has identified the commensal microbiota as a key determinant of anti-tumor immunity and immunotherapy efficacy in a mouse melanoma model (Sivan et al. Science 2015). Based on that work, we pursued a similar correlation in human melanoma patients undergoing anti-PD-1 immunotherapy and found a profound correlation between baseline microbiota composition and clinical response, which was a significant biomarker for predicting treatment outcome (Matson et al. Science 2015). We further demonstrated a deeper causal link by colonizing germ-free mice with responder or non- responder patient microbiomes, which recapitulated the strong or poor therapeutic response to PD-1 blockade, which correlated with the degree of spontanaoues T cell priming against the tumor. In the current proposal, we will employ this model system to further pursue the mechanisms by which the commensal microbiota from humans modulates the anti-tumor immune response in vivo. A major goal is to identify the gut microbiota-driven messenger(s) capable of transmitting the immunomodulatory effect to the tumor site. Understanding these deeper mechanisms of immune potentiation could enable development of drugs that mimic the presence of immune-potentiating bacteria. Another major goal is to isolate and culture the human-derived commensal bacteria with immune-potentiating properties. This effort could lead to the development of probiotics to supplement immunotherapy regimens and improve outcomes in the future.
Our recent studies indicate that the commensal microbiota can modulate anti- tumor immunity and immunotherapy efficacy. The purpose of the proposed research is to identify mechanisms, via which gut bacteria modulate anti-tumor immunity, and to isolate and culture human-derived commensals with immune potentiating properties. Successful completion of the proposed research could enable the development of supplemental therapies, such as formulations of immune-potentiating commensal bacteria or synthetic drugs that mimic the presence of such bacteria, ultimately leading to improved immunotherapeutic outcomes in the clinic.