Characterization of brain metastasis-specific CD8+ T cells

项目摘要/摘要 CD8 T细胞是一种细胞毒T淋巴细胞，可直接杀伤肿瘤和病毒感染细胞。T细胞耗竭，in CD8T细胞对细胞的杀伤能力受损，与病毒和癌症的长期接触有关 抗原，并防止最佳疾病控制。免疫检查点阻断(ICB)针对CTLA-4或 PD-1途径使耗尽的CD8 T细胞恢复活力，促进肿瘤细胞杀伤。多项试验已经 证实了ICB在缩小或消除肿瘤和延长生存方面的效果；然而， 与颅外肿瘤相比，颅内肿瘤对ICB治疗更难治。脑转移瘤会影响 癌症患者的数量很大，而且与总体存活率低有关。因此，新的战略 迫切需要改善已经转移到大脑的肿瘤的治疗。 新型免疫治疗药物的开发依赖于CD8 T细胞的详细特征 脑转移瘤的异质性。我的初步数据显示，CD8有三个不同的群体 T细胞在人脑转移中的作用，其中一种是由末端分化的转录决定的 表型。使用小鼠慢性感染模型，我还证明了大脑浸润性抗原- 特定的CD8T细胞具有独特的、组织特异性的转录表型，这种表型在一个亚群中是保守的 CD8T细胞对人脑转移瘤的侵袭作用。由于这种不同的基因表达模式，我 脑浸润性抗原特异性表达可能存在新的共抑制分子的假设 CD8T细胞。阻断这些分子可能会提高PD-1通路阻断的治疗效果 增强脑内耗尽的CD8 T细胞的效应功能。 这个项目有三个目标。首先，我将全面描述CD8 T细胞的表型 浸润性人脑转移瘤并确定与循环CD8 T细胞共享的克隆型 细胞对免疫疗法的治疗有反应。第二，我将识别差异表达的基因 通过ICB后CD8 T细胞的脑内渗透，并利用小鼠LCMV模型检测这些基因的功能 CD8 T细胞耗尽的症状。最后，这笔赠款将支持我从一名受训医生过渡到独立。 拉菲·艾哈迈德的实验室领导一个独立的研究小组。

PROJECT SUMMARY / ABSTRACT CD8+ T cells are cytotoxic T lymphocytes that directly kill tumor and virally-infected cells. T cell exhaustion, in which CD8+ T cells have impaired cell-killing capacity, occurs with prolonged exposure to viral and cancer antigens and prevents optimal disease control. Immune checkpoint blockade (ICB) targeting CTLA-4 or the PD-1 pathway reinvigorates exhausted CD8+ T cells to promote tumor cell killing. Multiple trials have demonstrated the efficacy of ICB in shrinking or eliminating tumors and prolonging survival; however, intracranial tumors are more refractory to ICB therapy than extracranial tumors. Brain metastases affect a significant number of cancer patients and are associated with poor overall survival. Therefore, novel strategies are urgently needed to improve the treatment of tumors that have metastasized to the brain. Development of novel immunotherapeutic agents relies on a detailed characterization of CD8+ T cell heterogeneity in brain metastases. My preliminary data show that there are three distinct populations of CD8+ T cells in human brain metastases, one of which is defined by a terminally differentiated transcriptional phenotype. Using a murine chronic infection model, I have also demonstrated that brain-infiltrating antigen- specific CD8+ T cells have a unique, tissue-specific transcriptional phenotype, which is conserved in a subset of the CD8+ T cells infiltrating human brain metastases. Because of this differential gene expression pattern, I hypothesize that there may be novel co-inhibitory molecules expressed by brain-infiltrating antigen-specific CD8+ T cells. Blocking these molecules may improve therapeutic efficacy of PD-1 pathway blockade and enhance the effector function of exhausted CD8+ T cells in the brain. This project has three goals. First, I will comprehensively characterize the phenotype of CD8+ T cells infiltrating human brain metastases and determine how clonotypes that are shared with circulating CD8+ T cells respond to treatment with immunotherapies. Second, I will identify genes that are differentially expressed by brain-infiltrating CD8+ T cells after ICB and test the function of these genes using the murine LCMV model of CD8+ T cell exhaustion. Finally this grant will support my transition to independence from a trainee in Dr. Rafi Ahmed’s lab, to leading an independent research group.