NOVEL HUMORAL AND CELLULAR BIOMARKERS OF AUTOIMMUNE DISEASES CAUSED BY IMMUNOTHERAPY

免疫疗法已经改变了广泛的人类恶性肿瘤的治疗前景。免疫 检查点抑制剂（ICI）是阻断免疫调节“检查点”受体的单克隆抗体， 细胞毒性T淋巴细胞相关蛋白4（CTLA-4），程序性细胞死亡1（PD-1），或其配体PD- L1。ICI在许多患者中产生持久的反应。然而，随着他们的成功， 通常引起广泛的免疫相关不良事件（irAE），如糖尿病酮症酸中毒（DKA） 或甲状腺疾病，似乎比最初预期的更频繁地发生。癌症的免疫毒性 免疫治疗发生在高达90%，而自身免疫性内分泌疾病发生在约50%的 接受CTLA-4和/或PD-1/PD-L1抗体治疗的患者。这些irAE可能是严重的，甚至是终身的- 威胁性，如DKA中出现的自身免疫性1型糖尿病（T1 D）和原发性肾上腺功能不全 由自身免疫性肾上腺素引起。最近的一项研究表明，ICI相关的自身免疫性疾病 糖尿病;超过50%的患者报告，其中一半患者出现DKA（50.2%）。因此，在本发明中， 需要可靠的生物标志物来准确地分层这些候选患者的irAE风险， 这些生物标志物可能指向新的分子途径，可以有针对性地预防 免疫检查点阻断引起的irAE（Aim II）。具体来说，我们将利用最先进的单细胞 平台，以调查和表征全面的表型和功能分析的系统 ICI诱导的内分泌病患者的细胞网络。贝勒大学为我们的学习提供了极大的便利 医学院免疫毒性工作组。了解免疫因素和生物标志物 与ICI介导的炎性毒性相关的研究将有助于识别和早期治疗 ICI诱导的irAE，这可能为自身免疫性内分泌疾病的病因和治疗提供新的见解 疾病

Immunotherapy has transformed the treatment landscape for a wide range of human malignancies. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block the immune regulatory “checkpoint” receptors, the Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), Programmed Cell Death 1 (PD-1), or its ligand PD- L1. ICIs produce durable responses in many patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs), such as diabetic ketoacidosis (DKA) or thyroid disease, appearing to occur more frequently than originally expected. Immunotoxicity from cancer immunotherapy occurs in up to 90%, whereas autoimmune endocrine diseases occur in approximately 50% of patients treated with antibodies to CTLA-4 and/or PD-1/PD-L1. These irAEs can be serious or even life- threatening, such as autoimmune type 1 diabetes (T1D) presenting in DKA, and primary adrenal insufficiency caused by autoimmune adrenalitis. A recent study showed a marked increase of ICI-related autoimmune diabetes; reported in over 50% of the patients, with half of these patients presenting in DKA (50.2%). Thus, reliable biomarkers are needed to accurately stratify the risk of irAEs in patients who are candidates for these therapies (Aim I); these biomarkers may point to novel molecular pathways that could be targeted to prevent irAEs caused by immune checkpoint blockade (Aim II). Specifically, we will utilize the state-of-the-art single-cell platforms to investigate and characterize the comprehensive phenotypic and functional analyses of systemic cellular networks in patients with ICI-induced endocrinopathies. Our studies are greatly facilitated by the Baylor College of Medicine Immunotoxicity Working Group. Understanding the immunologic factors and the biomarkers associated with ICI-mediated inflammatory toxicities will be useful for the identification and early treatment of ICI-induced irAEs, and it may provide new insights into the pathoetiology and treatment of autoimmune endocrine diseases.