Mechanism-rooted therapeutic strategies for immune-related toxicities induced by checkpoint inhibitors

项目摘要/摘要 尽管免疫检查点抑制剂(ICIS)正在给癌症治疗带来革命性的变化，但它们与 危及生命或器官的并发症，称为免疫相关不良事件(IrAE)。类固醇，一线 对于irAEs的治疗，显著地取消了ICIS的抗肿瘤效果；然而，我们对 支持irAEs发生和发展的机制和体征非常有限。此外， IrAEs之间改变的免疫的共性和个性从未被描述过。我们的临床 翻译研究表明，联合ICI治疗(细胞毒性T淋巴细胞- 相关抗原4(CTLA-4)和程序性细胞死亡蛋白1(PD-1)抑制剂)对急性髓细胞白血病严重程度的影响 关节炎-IRAE、结肠炎-IRAE和肺炎-IRAI与PD-1抑制剂单一治疗的比较。值得注意的是，T助手 (TH)在关节炎关节滑液、结肠炎结肠和 肺炎--如支气管肺泡灌洗。与此同时，我们的实验室也出现了关节炎、结肠炎和 肺炎-IRAE小鼠模型重述了患者的临床环境。重要的是，就像人类一样，Th17细胞 ICI诱导的关节炎(滑膜)、结肠炎(结肠)、 和ICI联合治疗后的肺炎(肺)，并与IRAE病情严重程度相关。有趣的是， 易患关节炎的小鼠在接受联合ICI的粪便微生物移植(FMT)后患上关节炎 关节炎捐赠者小鼠，特别是Th17细胞信号增强。我们还观察到，对Th17的封锁- 相关细胞因子白介素6和肿瘤坏死因子α可能与免疫反应有关。 保护/提高ICI疗法在人和小鼠中的抗肿瘤效果。进一步认识 IrAEs的潜在机制可能导致识别共同和有效的生物标志物预测 发展和/或反映irAEs的严重程度以及治疗方面的新步骤。因此，我们 建议揭示共同和独特的细胞/分子机制(S)支持irAEs(关节炎- IRAE、结肠炎-IRAE和肺炎-IRAE)的发展以及建立有效的治疗方法 战略。在这里，在目标1中，我们将通过以下方式确定细胞和分子机制和治疗靶点 利用我们新的临床前irAEs小鼠模型，包括关节炎、结肠炎和肺炎。此外, 关节炎癌症患者生物样本的细胞、表型和转录组分析， 结肠炎-IRAE或肺炎-IRAE有助于揭示常见或独特的免疫发病机制 在不同的irAe之间。在目标2中，我们将制定治疗irAEs的最佳策略，同时保留 利用黑色素瘤模型诱导irAEs小鼠抗肿瘤免疫。这项工作的影响将是 具有重要意义，并将有助于：1)发现irAE普遍或独特存在的机制；2)确定 反映IRAE疾病活动的机械性生物标志物；最重要的是，3)开发了一种 不牺牲抗肿瘤免疫的irAEs的治疗策略。

PROJECT SUMMARY/ABSTRACT Although immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment, they are associated with life- or organ-threatening complications, termed immune-related adverse events (irAEs). Steroids, the first-line of treatment for irAEs, significantly abrogate the anti-tumor efficacy of ICIs; however, our knowledge of the mechanisms and signs that underpin the onset and progression of irAEs is very limited. Furthermore, commonality and individuality of altered immunity between irAEs have never been characterized. Our clinical and translational studies have revealed significant impact of combined ICI therapy (cytotoxic T lymphocyte- associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors) on the severity of arthritis-irAE, -colitis-irAE, and -pneumonitis-irAE compared to PD-1 inhibitor monotherapy. Notably, T helper (Th)17 cell signatures were significantly enhanced in arthritis-irAE synovial fluid, colitis-irAE colon, and pneumonitis-irAE bronchoalveolar lavage. In parallel, our lab has developed arthritis-irAE, colitis-irAE and pneumonitis-irAE murine models recapitulating patients’ clinical settings. Importantly, like in humans, Th17 cell signatures were enriched in the inflamed tissue of mice with ICI-induced arthritis (synovium), colitis (colon), and pneumonitis (lung) after combined ICI-therapy and correlated with irAE disease severity. Interestingly, arthritis-prone mice developed arthritis after receiving fecal microbial transplant (FMT) from combined ICI arthritis donor mice, notably with enhanced Th17 cell signatures. We also observed that blockade of Th17- related cytokines, interleukin (IL)-6 and tumor necrosis factor alpha (TNFα), may pinpoint irAE immunity while preserving/enhancing the anti-tumor efficacy of ICI therapy in humans and mice. Further understanding of mechanisms underlying irAEs may lead to identification of common and valid biomarkers predicting development and/or reflecting severity of irAEs as well as to new steps in their treatment. Therefore, we propose to uncover shared and distinct cellular/molecular mechanism(s) underpinning irAEs (arthritis- irAE, colitis-irAE, and pneumonitis-irAE) development as well as establish efficient therapeutic strategies. Here, in Aim 1, we will identify the cellular and molecular mechanisms and therapeutic targets by utilizing our novel preclinical murine models of irAEs including arthritis, colitis, and pneumonitis. In addition, cellular, phenotypic, and transcriptomic analysis of biospecimens from cancer patients with arthritis-irAE, colitis-irAE or pneumonitis-irAE will help to uncover common or unique immunopathogenesis mechanisms between different irAEs. In Aim 2, we will develop optimal strategies for treatment of irAEs while preserving anti-tumor immunity by utilizing melanoma tumor model in mice with irAEs. The implications from this work will be significant and will help to: 1) discover mechanisms universally or distinctively present in irAEs; 2) identify mechanistic biomarkers reflecting irAE disease activity; and most importantly, 3) develop a mechanism-rooted therapeutic strategy for irAEs without sacrificing anti-tumor immunity.