The role of the gut microbiome in ICB-induced anti-tumor response and toxicity

肠道微生物组在 ICB 诱导的抗肿瘤反应和毒性中的作用

• 批准号: 10606715
• 负责人: Elizabeth M. Park
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606715
• 关键词: Affect; Anaerobic Bacteria; Antibiotic Therapy; Antibiotics; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antitumor Response; CD8-Positive T-Lymphocytes; CTLA4 gene; Cell Death; Cell physiology; Cells; Clinic; Clinical; Clinical Oncology; Clinical Research; Colitis; Combination immunotherapy; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Environment; Exhibits; Frequencies; Goals; Human; Immune; Immune response; Immune system; Immunologic Markers; Immunotherapy; Individual; Infiltration; Influentials; Innate Immune System; Intestines; Ligands; Link; Malignant Neoplasms; Mediating; Metronidazole; Microbe; Mus; Organ; PD-1/PD-L1; Patient-Focused Outcomes; Patients; Phenotype; Play; Population; Proteins; Role; Sampling; Survival Rate; T cell response; T-Cell Activation; Therapeutic; Tissues; Toxic effect; Translating; Tumor Immunity; Wild Type Mouse; Work; anti-PD-L1 therapy; anti-tumor immune response; cancer immunotherapy; cancer therapy; cancer type; cytokine; experience; experimental study; fecal transplantation; gut inflammation; gut microbiome; immune activation; immune checkpoint blockade; immune-related adverse events; improved; insight; melanoma; microbiome; microbiome composition; microbiome signature; mouse model; neoplastic cell; patient response; patient subsets; programmed cell death ligand 1; programmed cell death protein 1; response; training opportunity; treatment response; tumor; tumor growth; tumor immunology; unpublished works

PROJECT SUMMARY Immune checkpoint blockade (ICB) has transformed clinical oncology by inducing durable responses and increasing survival rates in many types of cancers, including melanoma. However, only a subset of patients benefits, and it is unclear what determines a patient’s response to therapy. In addition, ICB can lead to immune- related adverse events (irAEs) that limit therapy and cause off-target tissue toxicities. Combination therapy with anti-cytotoxic T-lymphocyte associated protein 4 (-CTLA-4) and anti-programmed death ligand 1 (-PD-L1) exhibits the strongest efficacy, in terms of survival, compared with single agent treatments, yet this is associated with a greater irAE frequency. Recent studies have delineated roles for the gut microbiome in serving as a biomarker of ICB responsiveness, a potential therapeutic, and in some cases association with irAEs. With this proposal, we aim to increase understanding of the gut microbiome-immune system axis in combination ICB therapy. Recent work from our lab has highlighted roles for dendritic cells (DCs), professional antigen-presenting cells (APCs) of the immune system, in ICB response as well as ICB-associated irAEs. Moreover, we found that modulation of the gut microbiome via antibiotic treatment altered response to -CTLA-4: use of metronidazole prior to ICB resulted in ~90% tumor regression upon -CTLA-4 treatment without intestinal irAE. In addition, the efficacy of -CTLA-4 in metronidazole treatment conditions was associated with increases in type 1 conventional DC (cDC1) amounts and activation status, consistent with prior clinical studies implicating a role for cDC1s in favorable ICB response in melanoma patients. Thus, we hypothesize that specific microbes within the gut microbiome induce increased activity of cDC1s, which regulate favorable responses to ICB treatment and, upon dysregulation, contribute to ICB-mediated colitis. We propose to examine this hypothesis in two aims. In Aim 1, we will identify the role of APCs in linking the gut microbiome to ICB-mediated anti-tumor immunity. We will utilize fecal samples from melanoma patients to repopulate the gut microbiome of antibiotic- treated mice (fecal microbiome transplantation, FMT). We will evaluate microbiome composition, immune cell profiles, and intestinal inflammation (irAEs) in melanoma-bearing mice treated with combination ICB. In addition, mice with a deficiency of cDC1s will be used to examine roles for this subset of APCs in ICB response and toxicity following FMT with patient-derived material. In Aim 2, we seek to characterize the relationship between metronidazole and effect on the microbiome and ICB response. We will utilize FMT with patient-derived material from non-responders and metronidazole treatment to examine whether depletion of anaerobic bacteria via metronidazole is sufficient to convert a non-responder into a responder. We will further examine the microbiome composition and identify links to immune cell status and activity upon metronidazole treatment. Our studies will delineate whether specific microbes from human fecal samples correlate with key immune signatures or irAEs, thereby deepening understanding of mechanisms by which the gut microbiome regulates ICB responsiveness.

项目摘要 免疫检查点阻断（ICB）通过诱导持久的反应和免疫应答改变了临床肿瘤学， 提高包括黑色素瘤在内的多种癌症的存活率。然而，只有一部分患者 目前还不清楚是什么决定了患者对治疗的反应。此外，ICB可导致免疫- 限制治疗并导致脱靶组织毒性的相关不良事件（irAE）。联合治疗 抗细胞毒性T淋巴细胞相关蛋白4（CD-CTLA-4）和抗程序性死亡配体1（CD-PD-L1） 与单药治疗相比，在生存方面表现出最强的疗效， 更高的irAE频率。最近的研究已经描绘了肠道微生物组在作为一种 ICB反应性的生物标志物，一种潜在的治疗方法，在某些情况下与irAE相关。与此 建议，我们的目标是增加对肠道微生物组免疫系统轴的理解，结合ICB 疗法我们实验室最近的工作强调了树突状细胞（DC）的作用， 在ICB反应以及ICB相关的irAE中，免疫系统的APC。此外，我们发现， 通过抗生素治疗调节肠道微生物组改变了对CTLA-4的反应：使用甲硝唑 在ICB之前，在没有肠irAE的情况下，在用β-CTLA-4治疗后导致~90%的肿瘤消退。此外该 在甲硝唑治疗条件下，CTLA-4的疗效与1型常规 DC（cDC 1）的数量和激活状态，与先前的临床研究一致，表明cDC 1在 黑色素瘤患者的ICB反应良好。因此，我们假设肠道内的特定微生物 微生物组诱导cDC 1活性增加，其调节对ICB治疗的有利反应 并且在失调时，导致ICB介导的结肠炎。我们建议在两个方面来检验这个假设 目标。在目标1中，我们将确定APC在将肠道微生物组与ICB介导的抗肿瘤作用联系起来中的作用。 免疫力我们将利用黑色素瘤患者的粪便样本来重新填充抗生素的肠道微生物组- 处理的小鼠（粪便微生物组移植，FMT）。我们将评估微生物组组成，免疫细胞 谱和肠道炎症（irAE）。此外，本发明还提供了一种方法， 将使用cDC 1缺陷的小鼠来检查该APC亚群在ICB应答中的作用， 使用患者源性材料进行FMT后的毒性。在目标2中，我们试图描述 甲硝唑以及对微生物组和ICB反应的影响。我们将使用患者源性材料的FMT 从无反应者和甲硝唑治疗，以检查是否耗尽厌氧菌通过 甲硝唑足以将无应答者转变为应答者。我们将进一步检查微生物组 组合物，并确定甲硝唑治疗后免疫细胞状态和活性的联系。我们的研究将 描述来自人类粪便样本的特定微生物是否与关键免疫特征或irAE相关， 从而加深对肠道微生物组调节ICB反应性的机制的理解。