Combating melanoma with an attenuated bacterial therapeutic

项目摘要/摘要 免疫疗法在治疗黑色素瘤方面取得了令人印象深刻的进展；然而，它的临床结果仍然存在。 受到各种病理生理因素的限制，如抑制性肿瘤微环境(TME)和 抗肿瘤免疫的关键分子决定因素仍然难以捉摸。发现新的和有效的 免疫调节靶点和涉及的机制将导致创新的战略，以增强 当前癌症免疫治疗的有效性。这样的发现是迫切需要的。之前的工作来自于此 研究小组表明，减毒的羊种布鲁氏菌突变体(即BMΔvjbR)显著改善了 抑制TME，并使用BMΔvJbR显著增强以过继细胞转移为基础的 免疫疗法。耐人寻味的是，用BMΔvJbR治疗后，这种安全、衰减的 在肿瘤组织中突变，极化M1巨噬细胞(Mφ)，并促进T细胞激活和产生 促炎症细胞因子；此外，将BMΔvJbR治疗与肿瘤抗原(Ag)特异性的ACT相结合 T细胞显着增强了肿瘤组织中M1、M、φ的积聚和T细胞的持久性。此外, 来自微生物区系的代谢物信号指示T细胞命运和功能；色氨酸(Trp)代谢物(例如， 羟基吲哚，HI)促进T细胞活性。最近的初步研究表明，与BMΔvjbR相比，a 产生HI的BMΔVJBR-HI株显著提高了肿瘤杀伤细胞因子(例如，TnFa， IFNG和颗粒酶B)，在黑色素瘤组织中积聚，并抑制肿瘤生长。它还戏剧性地 提高了动物的存活率。基于这些令人兴奋的初步数据，这个研究小组假设 工程化BMΔVJBR-HI将大大改善TME，靶向BMΔVJBR-HI可增强疗效 针对黑色素瘤的免疫疗法。这个多PI项目的总体目标是了解角色和 BMΔvJbR-HI调节TME和免疫耐药机制的研究 一种新的免疫调节靶点。该项目将追求以下三个高度相关和互动的 具体目的：(1)确定BM-ΔvJbR-HI在调节先天免疫中的作用和机制； 确定BMΔvJbR-HI在调节适应性免疫中的作用和机制；以及(3)确定其影响 BMΔvJbR-HI在黑色素瘤免疫治疗中的应用这一建议结合了癌症免疫学在 在De Figueiredo实验室和De Figueiredo实验室拥有微生物发病机制专业知识的Song实验室 在菲切特实验室发现疫苗的知识。研究团队已经建立了人性化的 小鼠(NOD-SCID IL2rgnull)肿瘤模型的实验室建立以及小鼠同基因系统的研究 学习。因此，他们准备实现上述目标。该项目的成功完成将 不仅揭示了工程BMΔvJbR-HI作为一种新型免疫调节剂改善TME的作用，并阐明了其 作用机制，但也提供了显著增强当前癌症的新治疗策略 免疫疗法。

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.