Developing strategies to inhibit cancer immunotherapy-induced immune-related adverse events without impeding anti-tumor immunity

项目摘要/摘要 肿瘤引发一系列的抑制机制，以逃避免疫系统。其中许多是 癌症免疫疗法的巨大成功证明了这一点是有针对性的，这种疗法提高了患者的自身免疫力 对癌症的反应。通常，癌症免疫治疗的靶点代表了体内平衡的途径。 防止自身免疫反应的激活，限制自身免疫的发展 疾病。接受免疫增强疗法治疗的癌症患者面临着极大的风险 出现免疫相关不良事件(IrAEs)。这些irAEs几乎在每个器官中都有报道。 系统，在许多情况下代表构成重大影响的未解决的自身免疫副作用 由于其潜在的发病率、死亡率和相关的医疗费用。随着越来越多的 免疫疗法达到临床实用，并增加可能启动更频繁的联合研究 和严重的irAEs，了解哪些治疗方法以最小的 副作用是必不可少的。在这项研究中，通过在自身免疫中产生可移植的、同基因的肿瘤细胞系- 倾向于NOD的小鼠，它们对癌症免疫治疗产生自身免疫病理反应，我们可能 开始评估irAEs与抗肿瘤免疫之间的相互作用。深入剖析遗传、表观遗传 以及分离抗肿瘤免疫和自身免疫以应对癌症的细胞机制 免疫疗法将被定义为更好地设计增强免疫反应的治疗策略 对肿瘤影响有限，对自身影响有限。使用对临床批准的癌症具有抗药性的NOD肿瘤 免疫疗法，如抗PD-1和抗CTLA-4，恢复活力的联合治疗策略 将确定肿瘤微环境中的免疫激活和沉淀的相关风险 确定了irAEs。总之，这些临床前模型为评估癌症的安全性提供了一个平台 免疫疗法，确定在保持抗肿瘤免疫的同时抑制或避免irAEs的机制。这 这项研究将在加州大学旧金山分校的世界级科学家和设施中进行 弗朗西斯科，这一环境将促进对生成的高维数据集的分析方面的专家培训 来自CyTOF和10X单细胞RNA和TCR测序，描述复合体的基本技能 导致免疫介导性疾病的机制。我的导师委员会，由杰弗里博士领导 蓝石和专家合作者将使我能够实现这些研究目标。接下来，我将过渡到 独立定位建立综合多种环境影响的研究计划 包括微生物群、饮食、年龄和压力在内的因素，以及自身免疫和抗肿瘤免疫反应 使用已经开发的NOD肿瘤模型进行癌症免疫治疗，最终目的是 提高接受免疫治疗的癌症患者的安全性、特异性和治疗效果。

Project Summary/Abstract Tumors elicit a range of suppressive mechanisms in order to evade the immune system. Many of these are targetable as evidenced by the great success of cancer immunotherapies that boost a patient's own immune response towards cancer. Often, targets for cancer immunotherapies represent pathways that at homeostasis protect against activation of an immune response towards self, limiting the development of autoimmune disease. Cancer patients treated with immune-potentiating therapies are exposed to significant risk of developing immune-related adverse events (irAEs). These irAEs have been reported in nearly every organ system, and in many cases represent non-resolving autoimmune side-effects that pose a significant impact due to their potential morbidity, mortality and associated healthcare costs. With a growing number of immunotherapies reaching clinical utility and increasing combination studies that may initiate more frequent and severe irAEs, understanding which therapeutic approaches provide improved tumor control with minimal side-effects is essential. In this study, by generating transplantable, syngeneic tumor cell lines in autoimmune- prone NOD mice, which develop autoimmune pathologies in response to cancer immunotherapies, we may begin to assess the interplay between irAEs and anti-tumor immunity. In-depth profiling of genetic, epigenetic and cellular mechanisms that separate anti-tumor immunity versus autoimmunity in response to cancer immunotherapies will be defined to better engineer therapeutic strategies that enhance the immune response towards tumor with limited impact towards self. Using NOD tumors resistant to clinically-approved cancer immunotherapies such as anti-PD-1 and anti-CTLA-4, combination therapeutic strategies that reinvigorate immune activation in the tumor microenvironment will be identified and the associated risk for precipitating irAEs determined. Together, these preclinical models provide a platform to assess safety profiles for cancer immunotherapies, identifying mechanisms to inhibit or avoid irAEs while preserving anti-tumor immunity. This research will be performed amongst world-class scientists and facilities at the University of California, San Francisco, this environment will foster expert training in the analysis of high-dimensional datasets generated from CyTOF and 10X single-cell RNA and TCR sequencing, an essential skill for delineating the complex mechanisms contributing to immune-mediated disease. Both my mentorship committee, led by Dr. Jeffrey Bluestone and expert collaborators will allow me to fulfil these research goals. Following, I will transition to an independent position establishing a research program that integrates the effect of multiple environmental factors, including microbiome, diet, age and stress, alongside autoimmune and anti-tumor immune responses to cancer immunotherapy using the NOD tumor models that have been developed, with the ultimate aim to improve safety, specificity and treatment efficacy for immunotherapy-treated cancer patients.