Combating melanoma with an attenuated bacterial therapeutic - PROJECT SUMMARY/ABSTRACT Immunotherapy has led to impressive advances in the treatment of melanoma; yet, its clinical outcomes remain limited by various pathophysiological factors, such as the suppressive tumor microenvironment (TME), and the key molecular determinants of antitumor immunity remain elusive. Discovering novel and effective immunomodulatory targets and the mechanisms involved would lead to innovative strategies for enhancing the effectiveness of current cancer immunotherapy. Such discoveries are urgently needed. Previous work from this research team showed that attenuated Brucella melitensis mutants (i.e., BmΔvjbR) substantially improved the suppressive TME, and the use of BmΔvjbR significantly enhanced adoptive cell transfer (ACT)-based immunotherapy. Intriguingly, treatment with BmΔvjbR resulted in the accumulation of this safe, attenuated mutant in tumor tissues, polarized M1 macrophages (Mφ), and promoted T cell activation and the production of proinflammatory cytokines; moreover, combining BmΔvjbR treatment with an ACT of tumor antigen (Ag)-specific T cells significantly enhanced the accumulation of M1 Mφ and T cell persistence in tumor tissues. In addition, metabolite signals from the microbiota instruct T cell fate and function; tryptophan (Trp) metabolites (e.g., hydroxyindoles, HI) promote T cell activity. Recent preliminary studies show that compared with BmΔvjbR, a BmΔvjbR-HI strain that produces HI dramatically improved production of tumor-killing cytokines (e.g., TNFa, IFNg and Granzyme B), accumulated in melanoma tissues, and suppressed tumor growth. It also dramatically improved animal survival. Based on these exciting preliminary data, this research team hypothesizes that engineered BmΔvjbR-HI will greatly improve the TME, and that targeting BmΔvjbR-HI can enhance the efficacy of immunotherapy for melanoma. The overall goals of this multiple-PI project are to understand the role and mechanism of BmΔvjbR-HI in modulating TME and immunotherapy resistance, and to establish this microbe as a novel immunomodulatory target. This project will pursue the following three highly related and interactive specific aims: (1) Determine the role and mechanism of BmΔvjbR-HI in modulating innate immunity; (2) Determine the role and mechanism of BmΔvjbR-HI in regulating adaptive immunity; and (3) Identify the impact of BmΔvjbR-HI on melanoma immunotherapy. This proposal combines the strength of cancer immunology in the Song laboratory with the expertise of microbial pathogenesis in the de Figueiredo laboratory and the knowledge of vaccine discovery in the Ficht laboratory. The research team has already established a humanized mouse (NOD-scid IL2rgnull) tumor model in the laboratory as well as murine syngeneic systems for the proposed studies. Therefore, they are poised to accomplish the above aims. Successful completion of this project would not only reveal engineered BmΔvjbR-HI as a novel immunomodulatory agent to improve TME and elucidate its mechanism of action, but also, provide new therapeutic strategies to significantly enhance current cancer immunotherapy.
