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

识别肠道细菌分子和促进免疫疗法抗肿瘤反应的机制

• 批准号: 10677530
• 负责人: Francesca Smylie Gazzaniga
• 金额: $ 18.71万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677530
• 关键词: Antibiotics; Antibodies; Antitumor Response; Bacteria; Bioinformatics; Biological; Blocking Antibodies; Breeding; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Cell Communication; Cell physiology; Cells; Cellular Assay; Chemistry; Clinic; Coculture Techniques; Collaborations; Colon; Combined Modality Therapy; Data; Dendritic Cells; Disease; Drug Industry; Environment; Epithelium; Exclusion; Flow Cytometry; Germ-Free; Gnotobiotic; Goals; Human Microbiome; Immune; Immune response; Immune system; Immunotherapy; In Vitro; Individual; Industry; Intestines; Ion-Exchange Chromatography Procedure; Knockout Mice; Label; Learning; Legal patent; Macrophage; Malignant Neoplasms; Mediating; Microbe; Microfluidics; Motivation; Mus; Organoids; PD-1 blockade; Pathway interactions; Patients; Play; Qualifying; Research; Role; Running; Signal Pathway; Signaling Molecule; Site; Sterility; Structure; Surface; T-Lymphocyte; T-bet protein; Testing; Therapeutic; Therapeutic Uses; Training; Translations; Tumor Immunity; Work; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD-L1 therapy; anti-cancer; anti-tumor immune response; cancer cell; cancer therapy; checkpoint therapy; clinical translation; commensal microbes; draining lymph node; experience; gastrointestinal epithelium; gut bacteria; gut microbes; gut microbiota; immune checkpoint; immune checkpoint blockade; in vivo; medical schools; mesenteric lymph node; microbiota; novel therapeutics; pharmacologic; pre-clinical; professional atmosphere; programmed cell death ligand 1; programmed cell death protein 1; response; skills; stem; therapeutically effective; transcriptome sequencing; tumor

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.

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， 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-L2。 CTLA 4）已经彻底改变了癌症治疗，但只有一小部分患者有反应。了解 促进对检查点阻断疗法的持久抗肿瘤应答的潜在机制至关重要 开发有效的治疗方法，可以治疗更广泛的癌症患者。肠道微生物群是关键 免疫治疗的抗肿瘤反应是可变的，即使是肠道外的肿瘤。这个目标 该项目的目的是鉴定促进PD-1阻断的抗肿瘤反应的肠道细菌分子及其 行动机制。我假设某些肠道细菌表面成分引发免疫细胞， 肠道内的这些细菌免疫相互作用对于PD-1的抗肿瘤免疫反应至关重要 肠外部位的阻滞。我建议通过确定关键的免疫成分来验证这一假设 肿瘤中微生物依赖的免疫反应（Aim 1），促进免疫反应的关键细菌分子， 抗肿瘤反应（目标2），以及微生物和免疫细胞在肿瘤内相互作用的机制。 肠（目标3）。这些研究意义重大，因为通过鉴定活性的抗肿瘤肠道细菌分子， 机制，可以开发更有效的治疗方法，这将扩大患者的范围， 对检查点疗法有反应。 我的长期目标是管理一个研究小组，研究肠道细菌和 免疫系统.我的动机是识别新的细菌分子及其作用机制， 可以在临床上用于治疗癌症和其他疾病。我在丹尼斯·卡斯帕的实验室受训 获得gnotobiotic小鼠工作，微生物群分析和培养，点击化学和细菌 分子分离导致目标1-3的初步数据。了解PD-1的免疫反应 阻断和共同信号分子，我与阿琳夏普的实验室合作，并获得了初步数据， 目标1-3。这种合作导致了两项专利申请和与工业界的讨论， 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， 我与哈佛韦恩斯研究所的唐纳德·英格伯实验室合作开发了一个芯片，我计划在Aims 2中使用它， 3.通过充分利用哈佛医学院优越的工作环境，我获得了 来自学术研究环境和行业经验的独特技能 讨论临床翻译。这项培训使我能够管理自己的研究小组， 肠道细菌/免疫相互作用，可用于创造新的治疗方法。