(8) Mechanisms of autoimmune endocrine diseases in patients receiving checkpoint inhibitors

总结 检查点抑制剂（CPI）疗法极大地改善了以前被认为是治疗癌症的方法。 被认为是棘手的。由于这些药物的预期生物活性，其能够激活T细胞， 细胞，可导致肿瘤破坏，新的自身免疫不良事件发生。这些主要目标 不良事件是内分泌组织，包括甲状腺和胰腺中的β细胞。甲状腺炎是 频繁的自身免疫性糖尿病已经成为一种严重的不良事件，经常需要加强护理。 一些个体发生这些自身免疫事件以及一些个体受到保护的原因并不清楚。 已知，但这些信息可能会导致预防这些不良事件发生的方法。整体 目的了解自身免疫性疾病的分子和细胞免疫学基础， 糖尿病和甲状腺疾病，并测试它们是否可以用特异性的药物来预防。 行动我们希望检验的假设是，在发生内分泌疾病的个体中，CPI治疗 诱导病理性T细胞、B细胞耐受性丧失和功能失调的调节性T细胞。我们的初步数据 已经确定了在那些做和不做的人中自身抗原反应性效应T细胞和T细胞的表型差异 而不是内分泌失调此外，我们对自身反应性B细胞的分析表明，CPI治疗 影响外周B细胞耐受性检查点，并导致自身反应性成熟 幼稚B细胞。我们计划使用Seq-Well单细胞分析前瞻性随访的患者， 从治疗前到出现自身免疫性内分泌病在那些 是HLA-A2（~40%），我们将使用细胞文库和CyTOF研究甲状腺和糖尿病反应性CD 8 + T细胞 并确定在抗原反应性细胞上发现的T细胞受体是否可以在 治疗和亚群。我们亦会研究消费物价指数是否影响 并具体说明CPI是否导致TCRs产生病理性细胞因子。我们将使用 确定CPI是否诱导外周B细胞耐受失败的已建立的技术， 确定B细胞变化与T细胞的关系。我们将收集自体反应T细胞的数据 和B细胞库，我们将与原发性肿瘤的临床反应相关联。最后，我们的研究 这些不良事件背后的免疫学机制表明， 预防，我们将在NOD小鼠中的抗PD-L1诱导的糖尿病的鼠模型中测试。我们将测试 无论是B细胞耗竭还是通过低剂量IL-2或通过输注糖尿病 抗原特异性TGFAP可预防糖尿病发作。因此，这些研究将阐明 这些严重不良事件，确定这些事件的最大风险个体，并测试是否 可以使用不干扰CPI的抗肿瘤作用的疗法来预防它们。

Summary Checkpoint inhibitor (CPI) therapy has greatly improved the treatment of cancers that had previously been considered intractable. As a result of the intended biologic activity of these drugs, which enable activation of T cells that can cause tumor destruction, new autoimmune adverse events have occurred. Major targets of these adverse events have been endocrine tissues including thyroid and beta cells in the pancreas. Thyroiditis is frequent and autoimmune diabetes has emerged as a serious adverse event often requiring intensive care. The reasons why some individuals develop these autoimmune events and why some are protected are not known but this information may lead to ways of preventing the occurrence of these adverse events. The overall objective if this proposal is to understand the molecular and cellular immunologic basis for autoimmune diabetes and thyroid disease and to test whether they can be prevented with agents that are specific in their actions. The hypothesis that we wish to test is that in individuals who develop endocrinopathies CPI therapy induces pathologic T cells, loss of B cell tolerance, and dysfunctional regulatory T cells. Our preliminary data has identified phenotypic differences in autoantigen reactive effector T cells and Tregs in those who do and do not develop endocrinopathies. In addition, our analysis of autoreactive B cells suggests that CPI therapy affects peripheral B cell tolerance checkpoints and results in an increased frequency of autoreactive mature naïve B cells. We plan to analyze, using Seq-Well single cells in patients who are followed prospectively from before treatment to when they present with autoimmune endocrinopathies. In the subgroup of individuals who are HLA-A2 (~40%) we will study thyroid and diabetes reactive CD8+ T cells with cellular libraries and CyTOF and determine whether the T cell receptors that are found on the antigen reactive cells can be detected prior to treatment and in which subpopulation. We will also determine whether CPIs affect the number and function of Tregs and address specifically whether the CPI causes the Tregs to produce pathologic cytokines. We will use established techniques to determine whether the CPIs induce a failure of peripheral B cell tolerance and identify the relationship between changes in B cells and Tregs. We will be collecting data on the autoreactive T and B cell repertoire that we will correlate with clinical responses to the primary tumors. Finally, our studies of the immunologic mechanisms that underlie these adverse events suggest ways in which they may be prevented, which we will test in a murine model of anti-PD-L1 induced diabetes in NOD mice. We will test whether B cell depletion or enhancement of Tregs, either by low doses of IL-2 or by infusion of diabetes antigen specific Tregs can prevent diabetes onset. These studies therefore, will elucidate the mechanisms of these serious adverse events, identify individuals who are at greatest risk for these events, and test whether therapies that do not interfere with the anti-tumor effects of the CPIs can be used to prevent them.