Identifying gut bacterial molecules and mechanisms that promote an anti-tumor response to immunotherapy

项目摘要 免疫系统能够产生强大的抗癌反应。然而，癌细胞可以 破坏这种免疫反应，劫持免疫检查点机制，作为刹车 内源性抗癌反应。阻断免疫检查点的抗体(例如，a-PD-L1、a-PD-1和a-PD-1) CTLA4)给癌症治疗带来了革命性的变化，然而，只有一小部分患者有反应。了解 促进对检查点阻断治疗的持久抗肿瘤反应的潜在机制至关重要 开发有效的疗法，可以治疗更广泛的癌症患者。肠道微生物区系是关键 免疫疗法的抗肿瘤反应不同，即使对肠道外的肿瘤也是如此。这样做的目的是 该项目是识别促进PD-1阻断的抗肿瘤反应的肠道细菌分子及其 行动机制。我推测某些肠道细菌表面成分启动免疫细胞和 肠道内的这些细菌-免疫相互作用对于PD-1的抗肿瘤免疫反应是必不可少的。 在肠外部位进行封锁。我建议通过确定关键的免疫成分来检验这一假设 肿瘤中的微生物依赖的免疫反应(目标1)，促进 抗肿瘤反应(目标2)，以及微生物和免疫细胞在体内相互作用的机制 Gut(目标3)。这些研究具有重要意义，因为通过识别活性的、抗肿瘤的肠道细菌分子和 机制，可以开发出更有效的治疗方法，扩大患者的范围 对检查点治疗有反应。 我的长期目标是领导一个研究小组，研究肠道细菌和细菌之间的相互作用 免疫系统。我的动机是识别新的细菌分子及其作用机制， 可在临床上用作癌症和其他疾病的治疗药物。我在丹尼斯·卡斯珀的实验室接受培训 获得诺生菌鼠标工作、微生物区系分析和培养、点击化学和细菌方面的专业知识 分子分离导致了AIMS 1-3的初步数据。了解PD-1的免疫应答 阻断和共信号分子，我与Arlene Sharpe的实验室合作，获得了 目标1-3。这种合作导致了两项专利申请，并与制药行业进行了讨论 翻译。为了了解细菌如何直接与肠道细胞相互作用，我开发了一种小鼠微流体肠道 与哈佛大学怀斯研究所的Donald Ingber实验室合作开发的芯片，我计划在AIMS 2和 3.利用哈佛医学院优越的工作环境，我获得了 独特的技能组合源于对学术研究环境和行业的经验 关于临床翻译的讨论。这次培训使我能够管理自己的研究小组，将调查 肠道细菌/免疫相互作用，可用于创造新的治疗方法。

Project Summary The immune system is capable of mounting a robust anti-cancer response. However, cancer cells can disrupt this immune response, hijacking immune checkpoint mechanisms which act as brakes on the endogenous anti-cancer response. Antibodies that block immune checkpoints (e.g., a-PD-L1, a-PD-1, and a- CTLA4) have revolutionized cancer treatments, yet, only a fraction of patients respond. Understanding the underlying mechanisms that promote a durable anti-tumor response to checkpoint blockade therapy is crucial to develop effective therapeutics that can treat a wider range of cancer patients. The gut microbiota is a key variable in the anti-tumor response to immunotherapy, even for tumors outside of the intestine. The goal of this project is to identify gut bacterial molecules that promote an anti-tumor response to PD-1 blockade and their mechanisms of action. I hypothesize that certain gut bacterial surface components prime immune cells and these bacterial-immune interactions within the gut are essential for the anti-tumor immune response to PD-1 blockade at extra-intestinal sites. I propose to test this hypothesis by determining the key immune components of the microbe-dependent immune response in the tumor (Aim 1), the key bacterial molecules which promote the anti-tumor response (Aim 2), and the mechanisms by which microbes and immune cells interact within the gut (Aim 3). These studies are significant because by identifying active, anti-tumor gut bacterial molecules and mechanisms, more effective therapeutics can be developed that will broaden the range of patients who respond to checkpoint therapy. My long-term goal is to run a research group that investigates the interactions between gut bacteria and the immune system. My motivation is to identify new bacterial molecules and their mechanisms of action that can be harnessed in the clinic as therapeutics for cancer and other diseases. I trained in Dennis Kasper’s lab gaining expertise in gnotobiotic mouse work, microbiota analysis and culture, click chemistry, and bacterial molecule separation leading to the preliminary data for Aims 1-3. To learn about the immune response to PD-1 blockade and co-signaling molecules, I collaborated with Arlene Sharpe’s lab and obtained preliminary data for Aims 1-3. This collaboration has led to two patent applications and discussions with industry for drug translation. To understand how bacteria directly interact with gut cells, I developed a mouse microfluidic gut chip in a collaboration with Donald Ingber’s lab at the Wyss institute at Harvard that I plan to use in Aims 2 and 3. By taking advantage of the excellent work environment at Harvard Medical School, I have acquired a unique skill set stemming from experience with both the academic research environment and with industry discussions for clinical translation. This training enables me to run my own research group that will investigate gut bacterial/immune interactions that can be employed to create novel therapeutics.