Augmenting cancer checkpoint immunotherapies via microbially-derived metabolites

项目摘要/摘要 免疫检查点抑制剂(ICIS)显著提高了不同癌症类型的长期存活率 包括黑色素瘤、非小细胞肺癌、三阴性乳腺癌等。然而，ICI的疗效 依赖于多种癌症、宿主和环境变量，只有一小部分患者会对 这些抗体药物。因此，改善ICI反应性的方法是一个非常可取的、未得到满足的临床 需要。人类相关微生物是宿主健康和疾病(包括癌症治疗)的关键调节者。 临床研究表明，特定的肠道细菌种类与改善ICI患者的预后相关 这些活性微生物的治疗和定植可以直接在临床前动物中诱导抗肿瘤活性 模特们。这些观察提出了一个基本问题：决定ICI的微生物机制是什么 效果如何？我以前的工作已经证明，分泌的细菌肽聚糖水解酶足以 在小鼠癌症模型中广泛改进ICI治疗。此外，这种表型可以简单地概括出来。 通过共同注射模拟肽聚糖水解酶产物的合成片段。这些 这一发现提出了一个令人兴奋的假设，即微生物代谢产物的产生可以直接改善ICI。 功效。我建议的主要目标是研究细菌PG代谢物的酶动员，如 癌症ICI治疗中免疫调节的一般机制。目标1将探索宿主酶作为新的 决定ICI疗效的因素。AIM 2将生产化学探针来发现激活ICI的细菌 酵素。目标3将研究PG动员作为一种广谱策略来增强新的ICI反应 并针对新的检查站目标。为了实现这些目标，我建立了一个广泛的和 从我与Linda Hsieh-Wilson博士在化学工具开发方面的研究生工作中获得的跨学科技能 加州理工学院和我与霍华德博士在宿主-微生物交流和癌症免疫学方面的博士后工作 在斯克里普斯研究中心工作。为了补充这些优势，我与以下领域的领导人建立了合作 癌症免疫治疗和宿主-微生物相互作用领域提供新癌症模型系统的培训 以及获得关键的人类来源的分离株，这将极大地帮助我努力建立一般性和 脑梗塞治疗期间PG动员的人类相关性。此外，我还提出了一个全面的职业生涯 制定发展计划，以解决我在有效管理实验室、传播 我们的发现，并获得独立的资金。在K22期间获得这些技能将会推动 在完成我的提案方面取得了进展，提供了我的第一个NCI R01所需的关键初步数据 批准申请。K22奖为我带来的科学和职业发展将帮助我实现我的 长期的职业目标是在宿主和微生物的交汇点成为一名成功的独立调查员 通讯和癌症免疫治疗。此外，这些努力可能会产生机械性的见解和 在临床上理解和增强不同的ICI反应的翻译途径。

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) have significantly improved long-term survival across diverse cancer types including melanoma, non-small cell lung cancer, triple negative breast cancer, and others. However, ICI efficacy relies on multiple cancer, host, and environmental variables, and only a small fraction of patients will respond to these antibody drugs. Methods to improve ICI responsiveness are therefore a highly desirable, unmet clinical need. Human-associated microbes are critical regulators of host health and disease including cancer treatment. Clinical studies have shown that specific gut bacterial species correlate with improved patient outcomes of ICI therapy, and colonization by these active microbes can directly elicit antitumor activity in preclinical animal models. These observations raise a fundamental question: what are the microbial mechanisms that dictate ICI efficacy? My previous work has demonstrated that a secreted bacterial peptidoglycan hydrolase is sufficient to broadly improve ICI therapy in murine models of cancer. Moreover, this phenotype could be recapitulated simply by coadministration of a synthetic fragment that mimics the product of the peptidoglycan hydrolase. These findings raise the exciting hypothesis that the production of microbial metabolites can directly improve ICI efficacy. The main objective of my proposal is to examine enzymatic mobilization of bacterial PG metabolites as a general mechanism of immune modulation during cancer ICI therapy. Aim 1 will explore host enzymes as new factors that determine ICI efficacy. Aim 2 will produce chemical probes to discover ICI-activating bacterial enzymes. Aim 3 will examine PG mobilization as a broad-spectrum strategy to potentiate ICI response in new indications and against new checkpoint targets. To accomplish these goals, I have built a broad and interdisciplinary skill set from my graduate work in chemical tool development with Dr. Linda Hsieh-Wilson at Caltech and my postdoctoral work in host-microbial communication and cancer immunology with Dr. Howard Hang at Scripps Research. To complement these strengths, I have established collaborations with leaders in the fields of cancer immunotherapy and host-microbial interactions to provide training in new cancer model systems and access to critical human-derived isolates, which will greatly aid in my efforts to establish the generality and human relevance of PG mobilization during ICI treatment. In addition, I have proposed a comprehensive career development plan to address any residual gaps in my abilities to effectively manage a laboratory, disseminate our findings, and obtain independent funding. The acquisition of these skills during the K22 period will fuel progress towards the completion of my proposal, providing key preliminary data needed for my first NCI R01 grant application. My scientific and career development enabled by the K22 award will help me to achieve my long-term career goal to become a successful independent investigator at the intersection of host-microbial communication and cancer immunotherapy. Moreover, these efforts may yield mechanistic insights and translational avenues to understand and augment differential ICI responses in the clinic.