NOVEL HUMORAL AND CELLULAR BIOMARKERS OF AUTOIMMUNE DISEASES CAUSED BY IMMUNOTHERAPY

免疫疗法已经改变了一系列人类恶性肿瘤的治疗格局。免疫 检查点抑制因子(ICIS)是一种能阻断免疫调节的“检查点”受体的单抗。 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-1- L1。ICIS在许多患者中产生持久的反应。然而，加上他们的成功，这些治疗方法 通常会引起广泛的免疫相关不良事件，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。癌症的免疫毒性 免疫疗法的发生率高达90%，而自身免疫性内分泌疾病的发生率约为50%。 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，甚至是生命- 威胁，如自身免疫性1型糖尿病(T1D)出现在DKA中，以及原发性肾上腺功能不全 由自身免疫性肾上腺炎引起。最近的一项研究表明，与ICI相关的自身免疫显著增加 糖尿病；报道了超过50%的患者，其中一半的患者出现在DKA(50.2%)。因此， 需要可靠的生物标记物来准确地对这些患者的irAEs风险进行分层。 治疗(目标I)；这些生物标志物可能指向新的分子途径，可以靶向预防 免疫检查点阻断引起的irAEs(AIM II)。具体地说，我们将利用最先进的单细胞 研究和表征系统的全面表型和功能分析的平台 ICI所致内分泌疾病患者的细胞网络。贝勒夫妇极大地促进了我们的学习。 医学院免疫毒性工作组。了解免疫学因素和生物标志物 与ICI介导的炎症毒性相关将有助于识别和早期治疗 ICI诱导的irAEs，可能为自身免疫内分泌的发病机制和治疗提供新的思路。 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.