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., Bm¿vjbR) substantially improved the
suppressive TME, and the use of Bm¿vjbR significantly enhanced adoptive cell transfer (ACT)-based
immunotherapy. Intriguingly, treatment with Bm¿vjbR resulted in the accumulation of this safe, attenuated
mutant in tumor tissues, polarized M1 macrophages (Mf), and promoted T cell activation and the production of
proinflammatory cytokines; moreover, combining Bm¿vjbR treatment with an ACT of tumor antigen (Ag)-specific
T cells significantly enhanced the accumulation of M1 Mf 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 Bm¿vjbR, a
Bm¿vjbR-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 Bm¿vjbR-HI will greatly improve the TME, and that targeting Bm¿vjbR-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 Bm¿vjbR-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 Bm¿vjbR-HI in modulating innate immunity; (2)
Determine the role and mechanism of Bm¿vjbR-HI in regulating adaptive immunity; and (3) Identify the impact
of Bm¿vjbR-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 Bm¿vjbR-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.