Endocrine tissue molecular pathways dysregulated by immune checkpoint inhibitors causing ICI-triggered adverse events

免疫检查点抑制剂导致内分泌组织分子通路失调，导致 ICI 引发的不良事件

• 批准号: 10648465
• 负责人: MIHAELA STEFAN-LIFSHITZ
• 金额: $ 23.56万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648465
• 关键词: Acceleration; Adrenergic beta-Antagonists; Adverse effects; Adverse event; Affect; Apoptosis; Autoimmunity; Autophagocytosis; Biological Assay; Biotin; Cell Line; Cell Survival; Cells; Cellular Stress; Cessation of life; Development; Endocrine; Exposure to; Functional disorder; Goals; Human; Hypothyroidism; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunological Models; Immunotherapy; Induction of Apoptosis; Inflammation; Inflammatory; Interferon Type II; Interferons; Ligands; Ligation; Light; Malignant Neoplasms; Mediating; Mediator; Mitochondria; Molecular; Monoclonal Antibodies; Mus; Organ; Pathway interactions; Patients; Phase; Predisposition; Proteins; Regulator Genes; Role; Signal Transduction; Sirolimus; Stress; T-Cell Activation; T-Lymphocyte; Testing; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyroiditis; Tissues; Toxic effect; Translating; Up-Regulation; anti-PD-L1; cancer cell; cancer therapy; checkpoint therapy; cytokine; design; endoplasmic reticulum stress; experience; immune activation; immune-related adverse events; immunoregulation; mouse model; multidisciplinary; mutant; new therapeutic target; novel therapeutics; overexpression; prevent; programmed cell death ligand 1; programmed cell death protein 1; protective effect; receptor; response; restoration; therapeutically effective

Project Summary/Abstract Programed death ligand-1 (PD‐L1) is an immune checkpoint inhibitor (ICI) that interacts with its receptor, programmed death‐1 (PD‐1) to inhibit T‐cell activation. Cancer cells adapted to manipulate this mechanism, by overexpressing PD-L1 to evade immune activation and attack. Therefore, abrogation of PD-L1/PD-1 interaction by monoclonal antibodies (MAb’s) is an effective therapeutic strategy for several cancers. However, it is complicated by immune related adverse events (irAEs), including endocrine AEs (eAEs). Thyroid dysfunction, including destructive thyroiditis and hypothyroidism, are the most common eAEs associated with PD-L1/PD-1 blockade, affecting up to 21% of patients. Because their mechanisms are not known, currently these conditions are treated symptomatically and as a result, patients are often difficult to manage, and the eAEs can interfere with the cancer treatment. Therefore, new therapies are needed that target the mechanisms causing eAEs. We have found that PD-L1, expressed in the thyroid, exerts intrinsic functions in thyroid cells. We have generated human thyroid cell lines with either downregulated or increased PD-L1 expression and demonstrated that PD- L1 engages cell survival mechanisms in response to inflammatory cytokine-induced stress. Suppression of PD- L1 in thyroid cells rendered them more susceptible to cellular stress and apoptosis induced by inflammatory cytokines. The intrinsic functions of PD-L1 in thyrocytes and their role in the development of ICI thyroiditis have not been studied before. In this proposal we will dissect the immune-independent functions of PD-L1 in thyroid cells and their role in the development of ICI-thyroiditis. Our hypothesis is that blockade of PD-L1 in thyroid cells through anti-PD-L1 therapies, triggers dysregulation of pro-survival intracellular signals controlled by PD-L1, rendering thyrocytes vulnerable to cytokine mediated destruction. In Aim 1 we will perform cellular and molecular studies in thyroid cell lines with upregulated and downregulated PD-L1 expression to dissect the intracellular functions of PD-L1 by assessing: (1) Molecular mediators of PD-L1 intrinsic activity (e.g., signals delivered through the PD-L1 intracytoplasmic domain); (2) The role of PD-L1 in cellular responses to inflammatory stress; and (3) The downstream effectors of PD-L1 activity. In Aim 2 we will use a new mouse model of anti-PD-L1 induced thyroiditis we developed to test: (1) How inflammatory cytokines affect the development of anti-PD-L1 induced thyroiditis; and (2) The possibility of reversing/suppressing thyroiditis in this mouse model by restoring autophagy in thyroid cells. In summary, we are proposing a “two-hit” model for ICI thyroiditis whereby PD- L1 blockade triggers both: (1) Activation of intra-thyroidal T-cells & inflammatory cytokine secretion; and (2) Dysregulation of thyrocyte intra-cellular signals making them susceptible to inflammatory cytokine damage. In this proposal we will dissect the nonimmune roles for PD-L1 in thyroid cells and extend the understating of the “off-target” effects of anti-PD-L1 immunotherapy. Our studies will hopefully help design targeted mechanism- based therapies for ICI associated adverse events in the thyroid and other organs.

项目摘要/摘要 程序性死亡配体1（PD-L1）是一种免疫抑制剂（ICI），与其接收器相互作用， 编程死亡-1（PD -1）抑制T细胞激活。通过适应这种机制的癌细胞， 过表达PD-L1以逃避免疫激活和攻击。因此，废除PD-L1/PD-1相互作用 单克隆抗体（MAB）是几种癌症的有效治疗策略。但是，是 与免疫相关的不良事件（IRAE）复杂化，包括内分泌AES（EAES）。甲状腺功能障碍， 包括破坏性甲状腺炎和甲状腺功能减退症，是与PD-L1/PD-1相关的最常见的EAS 封锁，影响多达21％的患者。因为它们的机制尚不清楚，所以目前这些条件 受到症状的治疗，结果，患者通常难以管理，EA可以干扰 进行癌症治疗。因此，需要新的疗法来靶向引起EAS的机制。我们 已经发现在甲状腺中表达的PD-L1在甲状腺细胞中发挥内在功能。我们已经生成了 人类甲状腺细胞系具有下调或增加的Pd-L1表达，并证明PD- L1响应炎症细胞因子诱导的应激而使细胞存活机制参与。抑制Pd- 甲状腺细胞中的L1使它们更容易受到细胞应激和炎症引起的凋亡 细胞因子。 PD-L1在甲状腺细胞中的固有功能及其在ICI甲状腺炎发展中的作用具有 以前没有研究。在此提案中，我们将剖析甲状腺中PD-L1的免疫独立功能 细胞及其在甲状腺炎发育中的作用。我们的假设是甲状腺细胞中PD-L1的封锁 通过抗PD-L1疗法，触发由PD-L1控制的促生存的细胞内信号的失调 使甲状腺细胞容易受到细胞因子介导的破坏的影响。在AIM 1中，我们将执行细胞和分子 在具有更新和下调的PD-L1表达的甲状腺细胞系中的研究以剖析细胞内 通过评估PD-L1的功能：（1）PD-L1内在活性的分子介质（例如，传递的信号 通过PD-L1内胞质内结构域）； （2）PD-L1在细胞对炎症应激的反应中的作用； （3）PD-L1活性的下游效应。在AIM 2中，我们将使用抗PD-L1的新鼠标模型 诱导的甲状腺炎我们开发了测试：（1）炎症细胞因子如何影响抗PD-L1的发展 诱导甲状腺炎； （2）通过恢复这种小鼠模型中逆转/抑制甲状腺炎的可能性 甲状腺细胞中的自噬。总而言之，我们提出了一种ICI甲状腺炎的“两击”模型，从而PD- L1阻断触发了这两者：（1）激活脑肌内T细胞和炎症细胞因子分泌； （2） 细胞内信号的失调，使其容易受到炎症性细胞因子损伤。在 该提案我们将在甲状腺细胞中剖析PD-L1的非免疫作用，并延伸低估的 抗PD-L1免疫疗法的“脱靶”作用。我们的研究有望帮助设计有针对性的机制 - 甲状腺和其他器官中ICI相关不良事件的基于基于ICI相关的不良事件的疗法。