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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要免疫系统能够产生强大的抗癌反应，但癌细胞却可以。破坏这种免疫反应，劫持免疫检查点机制，从而起到制动作用阻断免疫检查点的内源性抗癌反应抗体（例如 a-PD-L1、a-PD-1 和 a-） CTLA4）彻底改变了癌症治疗，但只有一小部分患者有反应。促进检查点阻断治疗持久抗肿瘤反应的潜在机制至关重要开发能够治疗更广泛癌症患者的有效疗法，肠道微生物群是关键。即使对于肠道外的肿瘤，免疫治疗的抗肿瘤反应也存在差异。该项目的目的是鉴定肠道细菌分子，促进对 PD-1 阻断的抗肿瘤反应及其我认为某些肠道细菌表面成分会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 的抗肿瘤免疫反应至关重要我建议通过确定关键的免疫成分来检验这一假设。肿瘤中微生物依赖性免疫反应（目标 1）的关键细菌分子，促进抗肿瘤反应（目标 2），以及微生物和免疫细胞在细胞内相互作用的机制这些研究意义重大，因为通过识别活性、抗肿瘤的肠道细菌分子和机制，可以开发更有效的治疗方法，扩大患者范围对检查点治疗有反应。我的长期目标是组建一个研究小组，研究肠道细菌和肠道细菌之间的相互作用。我的动机是识别新的细菌分子及其作用机制。可以在诊所中用作丹尼斯·卡斯珀实验室针对癌症和其他疾病的治疗方法。获得无菌小鼠工作、微生物群分析和培养、点击化学和细菌方面的专业知识分子分离产生目标 1-3 的初步数据了解 PD-1 的免疫反应。封锁和协同信号分子，我与 Arlene Sharpe 的实验室合作，获得了初步数据目标 1-3。此次合作促成了两项专利申请并与药物行业进行了讨论。为了了解细菌如何与肠道细胞直接相互作用，我开发了小鼠微流体肠道。与哈佛大学 Wyss 研究所的 Donald Ingber 实验室合作的芯片，我计划在 Aims 2 和 3. 利用哈佛医学院优良的工作环境，我获得了源自学术研究环境和行业经验的独特技能临床翻译的讨论使我能够管理自己的研究小组来进行调查。肠道细菌/免疫相互作用，可用于创造新的疗法。