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.

项目总结/文摘