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

项目总结/摘要： 尽管抗PD 1治疗非小细胞肺癌（NSCLC）获得了里程碑式的批准，但大多数 患者仍在进步。淋巴细胞活化基因3（LAG 3）的代偿性活化，以抑制T细胞 活化是癌症中对抗PD-1疗法的抗性的既定机制。我们最近的研究表明 IL-6是NSCLC患者LAG 3的上游诱导剂。我们已经证明了 接受抗PD-1治疗的NSCLC患者中IL-6和STAT 3活化与应答降低之间的关系 疗法然而，我们不知道（1）IL-6诱导LAG 3表达导致抗IL-6抗体的机制。 PD-1抗性，或（2）如果IL-6阻断防止体内T细胞功能障碍。本提案假设：（1） 增加的血浆IL-6通过外周CD 8 + T细胞中的STAT 3活化诱导LAG 3表达，导致T细胞凋亡。 细胞功能障碍和对抗PD-1治疗的应答降低;和（2）LAG 3介导的T细胞 功能障碍可以用体内IL-6阻断来挽救。这将对未来的研究产生重大影响。 关于癌症免疫疗法的抵抗力。具体来说，这个项目将告知我们对一个 新的IL-6诱导的LAG 3介导的抗PD-1抗性机制，并将作为临床前研究的一部分。 在早期临床试验中研究IL 6/STAT 3抑制和PD-1阻断的组合的基本原理 晚期NSCLC患者的临床试验。这项提案将为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， 体积和数量，以及（iii）通过以下方法评估鼠T细胞中的免疫景观： 免疫组织化学（IHC）和流式细胞术以及RNA测序（RNAseq）。他将继续他目前的 也可以处理病人的样本这些技能将得到导师，顾问，合作者， 以及北卡罗来纳州和匹兹堡大学的核心资源。主 导师Jonathan Serody博士是一位国际公认的NIH R 01资助的科学家，拥有28年的 Dario Vignali博士是NIH R 01资助的肿瘤免疫学家， 有几十年的鼠类研究经验此外，一个由有成就的调查人员组成的咨询委员会 凭借肿瘤免疫学的专业知识，IL-6，LAG 3，PD-1和NSCLC将监测Somasundaram博士的进展 与季度会议，以确保完成博士Somasundaram的短期目标的科学 独立性和长期目标，成为一个终身制的医生，科学家与系统的专业知识， 炎症、肿瘤免疫学、检查点阻断抗性和NSCLC。这一提议的结果 将为R 01研究NSCLC中IL 6诱导的抗PD-1耐药性的翻译作用奠定基础。

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.