The role of IL6-induced LAG3 as a resistance mechanism to PD1 blockade in NSCLC patients

IL6诱导的LAG3作为NSCLC患者PD1阻断耐药机制的作用

• 批准号: 10739491
• 负责人: Ashwin Somasundaram
• 金额: $ 27.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739491
• 关键词: Advisory Committees; Animal Model; Binding; Biological Assay; Biological Markers; Blood; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Carcinogens; Cell physiology; Cessation of life; Coculture Techniques; Combined Modality Therapy; Data; Disease Progression; Drug resistance; Ensure; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Flow Cytometry; Formalin; Freezing; Functional disorder; Funding; Future; Gene Activation; Goals; IL6 gene; IL6ST gene; Immune; Immunohistochemistry; Immunologist; Immunotherapy; In Vitro; Infiltration; Interleukin-6; International; Ketones; Link; Lymphocyte Activation; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mentors; Modeling; Monitor; Mus; Nicotine; Nitrosamines; Non-Small-Cell Lung Carcinoma; North Carolina; PD-1 blockade; Paraffin Embedding; Pathway interactions; Patients; Peripheral; Physicians; Plasma; Production; Progressive Disease; Proliferating; Prospective cohort; Proteins; Research; Research Personnel; Resistance; Resources; Role; Sampling; Scientist; Signal Pathway; Stat3 protein; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; United States National Institutes of Health; Universities; Work; anti-PD1 therapy; cohort; cytokine; cytotoxic CD8 T cells; design; early phase clinical trial; experience; immune checkpoint blockade; in vivo; meetings; mouse model; novel; pre-clinical; predictive marker; prevent; programmed cell death protein 1; resistance mechanism; response; response biomarker; skills; systemic inflammatory response; tenure track; therapy development; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor immunology

PROJECT SUMMARY/ABSTRACT: Despite the landmark approval of anti-PD1 therapy for non-small cell lung cancer (NSCLC), the majority of patients still progress. Compensatory activation of lymphocyte activation gene 3 (LAG3), to suppress T cell activation is an established mechanism of resistance to anti-PD-1 therapy in cancer. Our recent work suggests that IL-6 is an upstream inducer of LAG3 in patients with NSCLC. We have demonstrated an association between IL-6 and STAT3 activation and decreased response in patients with NSCLC receiving anti-PD-1 therapy. However, we do not know (1) the mechanism of IL-6-induced LAG3 expression which leads to anti- PD-1 resistance, or (2) if IL-6 blockade prevents T cell dysfunction in vivo. This proposal hypothesizes that (1) increased plasma IL-6 induces LAG3 expression via STAT3 activation in peripheral CD8+ T cells leading to T cell dysfunction and decreased response to anti-PD-1 therapy in patients; and (2) LAG3-mediated T cell dysfunction can be rescued with IL-6 blockade in vivo. This proposal will significantly impact future studies regarding immunotherapy resistance in cancer. Specifically, this project will inform our understanding of a novel IL-6-induced LAG3 mediated mechanism of anti-PD-1 resistance and will serve as the pre-clinical rationale for investigating the combination of IL6/STAT3 inhibition and PD-1 blockade in an early phase clinical trial for patients with advanced NSCLC. This proposal will provide Dr. Somasundaram with the opportunity to continue work with (i) animal models (design and oversee murine models), (ii) quantify changes in tumor size, volume and number in mice, and (iii) evaluate the immune landscape in murine T cells by immunohistochemistry (IHC) and flow cytometry, and RNA sequencing (RNAseq). He will continue his current work with patient samples also. These skills will be reinforced by a team of mentors, advisors, collaborators, and core resources available at the University of North Carolina and the University of Pittsburgh. The primary mentor, Dr. Jonathan Serody, is an internationally recognized, NIH R01-funded scientist with 28 years of experience in tumor immunology, and co-mentor, Dr. Dario Vignali, is an NIH R01-funded tumor immunologist with decades of experience in murine research. Also, an advisory committee of accomplished investigators with expertise in tumor immunology, IL-6, LAG3, PD-1, and NSCLC will monitor Dr. Somasundaram’s progress with quarterly meetings ensuring the completion of Dr. Somasundaram’s short-term goal of scientific independence and long-term goal of becoming a tenure-track physician-scientist with expertise in systemic inflammation, tumor immunology, checkpoint blockade resistance, and NSCLC. The results from this proposal will form the basis for an R01 studying the translational role of IL6 induced anti-PD-1 resistance in NSCLC.

项目摘要/摘要： 尽管非小细胞肺癌(NSCLC)的抗PD1疗法获得了里程碑式的批准，但大多数 患者的病情仍在好转。淋巴细胞激活基因3(LAG3)的代偿激活，抑制T细胞 激活是肿瘤对抗PD-1治疗产生抵抗的一种既定机制。我们最近的研究表明 提示IL-6是非小细胞肺癌患者LAG3的上游诱导物。我们已经证明了一种联系 非小细胞肺癌患者接受抗PD-1治疗后IL-6和STAT3激活与应答降低之间的关系 心理治疗。然而，目前尚不清楚(1)IL-6诱导LAG3表达从而导致抗肿瘤效应的机制。 PD-1抵抗，或(2)如果IL-6阻断体内T细胞功能障碍。这项提议假定(1) 血浆IL-6水平升高通过激活外周CD8+T细胞中的STAT3诱导LAG3表达 患者的细胞功能障碍和对抗PD-1治疗的反应性降低；以及(2)LAG3介导的T细胞 在体内，通过阻断IL-6可以挽救功能障碍。这一提议将对未来的研究产生重大影响。 关于免疫治疗在癌症中的耐药性。具体地说，这个项目将使我们了解到 IL-6诱导LAG3介导的抗PD-1耐药新机制及其临床前应用 在早期临床中研究IL6/STAT3抑制和PD-1阻断联合应用的理论基础 晚期非小细胞肺癌患者的试验。这项提议将为Somasundaram博士提供机会 继续研究(I)动物模型(设计和监督小鼠模型)，(Ii)量化肿瘤大小的变化， 小鼠的体积和数量，以及(Iii)通过以下方式评估小鼠T细胞的免疫状况 免疫组织化学(IHC)和流式细胞术，RNA测序(RNAseq)。他将继续他目前的工作。 也要处理患者样本。这些技能将得到由导师、顾问、合作者组成的团队的加强， 以及北卡罗来纳大学和匹兹堡大学的核心资源。初级阶段 导师乔纳森·塞罗迪博士是国际公认的NIH R01资助科学家，拥有28年的 在肿瘤免疫学方面的经验，以及共同导师Dario Vignali博士是NIH R01资助的肿瘤免疫学家 拥有数十年的老鼠研究经验。此外，一个由经验丰富的调查人员组成的咨询委员会 凭借在肿瘤免疫学方面的专业知识，IL-6、LAG3、PD-1和NSCLC将监测Somasundaram博士的进展 每季度举行一次会议，确保完成Somasundaram博士的短期科学目标 独立性和长期目标是成为一名拥有全身性专业知识的终身制医生-科学家 炎症、肿瘤免疫学、检查点阻断抵抗和非小细胞肺癌。这项提案的结果是 将为R01研究IL6诱导的抗PD-1耐药在非小细胞肺癌中的翻译作用奠定基础。