Engineering diverse commensal skin bacteria for targeted immunotherapy

PROJECT SUMMARY: Immune modulation is central to cancer therapy. A major challenge in the field is to develop an effective platform for stimulating potent, tumor-specific T cell immunity, which selectively destroys cancer cells but leaves healthy tissue intact. To address this challenge, we propose a novel cancer vaccination platform that uses engineered skin commensal bacteria to stimulate tumor-specific T cells. Our central hypothesis is that commensal stimulation of T cells is potent without toxicity, easily directable to our antigens of choice, and more precisely controls the functional subset of T cells generated. Our rationale is based upon our previous study, where we discovered a way to leverage Staphylococcus epidermidis (S. epi), a prevalent commensal skin bacterium that naturally stimulates CD8+ T cells upon colonization. In multiple murine cancer models, skin colonization by tumor antigen-expressing S. epi expanded tumor-specific T cells, which protected mice from both local and metastatic cancer and could synergize with immune checkpoint blockade without autoimmune sequelae. Critically, this work revealed that the immune response to a skin colonist can promote cellular immunity at a distal site. Further, it highlights the feasibility of redirecting this response against a therapeutic target of interest by expressing a target-derived antigen in a commensal bacterium. We now propose to expand our approach of commensal-based cancer immunotherapy. We will leverage innovative synthetic microbiology principles to overcome the barrier to progress of genetic intractability in a set of clinically relevant skin commensals. This will enable us to accomplish three major objectives: 1) express defined tumor antigens in a diverse set of skin commensals, 2) subsequently determine their in vivo T cell stimulatory capabilities by using our existing workflow, and 3) engineer the most stimulatory commensals into a potent anti-cancer T cell vaccine, for testing within multiple models of subcutaneous and metastatic cancer. Thus, will answer fundamental questions about commensal immunity and identify new skin commensal bacteria that induce CD8+ T cells, increasing the available “vehicles” for commensal-based therapeutics. The tools developed will also be useful for screening antigen-specific T cell stimulation by undomesticated bacteria from all body sites. Upon successful completion of this proposal, we will have generated a novel vaccination platform for cancer using engineered live commensal skin bacteria.