RNA Polymerase III specific CD8+ T cells: a mechanistic insight into cancer-induced autoimmunity in scleroderma

项目摘要/摘要 越来越多的证据表明，癌症和自身免疫之间存在免疫学联系。免疫系统是 能够通过识别改变的自身抗原来拒绝癌症；然而，健康人对自身抗原的识别 组织可能导致自身免疫。硬皮病或系统性硬化症(SSC)提供了一个独特的机会 研究这种关系，因为患有RNA聚合酶III(RPC1)自身抗体的患者风险增加 癌症的发生与SSC的发病同时发生。基因改变(体细胞突变或杂合性缺失，杂合性缺失) 在抗RPC1 SSC的癌症中发现了RNA聚合酶III基因座(蛋白质名称RPC1) 患者和不同群体的CD4T细胞被检测到识别正常和突变版本的 RPC1。综上所述，这些观察表明，针对突变的RPC1蛋白启动了抗肿瘤免疫 可以与野生型蛋白发生交叉反应，导致SSC。而CD4T细胞在协调抗病毒方面起着关键作用 肿瘤免疫应答中，CD8T细胞是清除肿瘤细胞的关键。此外，观测到的LOH 提示在这些患者中发生了由RPC1特异性CD8 T细胞驱动的肿瘤免疫编辑，并且在 与此同时，越来越多的证据表明CD8 T细胞参与了SSC的发病。一个重要的杰出人物 问题仍然是：是否可以在SSC和癌症患者中识别RPC1特异性细胞毒性T细胞。 这项建议旨在研究外周血和靶组织中RPC1特异的CD8 T细胞。 患有SSc和癌症的患者。AIM 1将检测RPC1特异的CD8 T细胞，这些细胞直接参与这两个过程 肿瘤部位的抗肿瘤反应以及受影响皮肤组织的自身免疫损伤 来自SSC患者。在目标2中，RPC1特异性CD8 T细胞的频率、表型和效应分子 将被研究并与癌症状况相关。最后，目标3将检查抗RPC1的效果 交叉呈现上的自身抗体，以及抗RPC1 SSC患者与 没有癌症病史。这项研究的结果将为今后探索 CD8T细胞对RPC1的应答可作为靶向监测工具和RPC1CD8T细胞表位 作为SSC的抗原特异性免疫疗法，以及为其他癌症相关风湿病的研究提供信息 疾病。这份K08提案旨在促进候选人的职业发展成为一名独立的 调查员。为了成功地实施这一提议，她组建了一支出色的导师团队，每个人 她为她的项目和她的科学发展带来了独特的专业知识。此外，这项提议需要 约翰霍普金斯硬皮病中心丰富的资源优势。建立在候选人之前的 研究抗原特异性T细胞免疫学和抗原处理的经验，这个K08奖将使她 为了获得对进行翻译免疫学很重要的生物信息学方面的更多技能，开发专业知识 在自身反应性CD8 T细胞与自身免疫和癌症相关的特定利基中，并获取数据 以及支持强大的R01应用程序所需的出版物。

PROJECT SUMMARY/ABSTRACT Increasing evidence suggests an immunologic link between cancer and autoimmunity. The immune system is able to reject cancer through recognition of altered self-antigens; however, recognition of self-antigens in healthy tissues could lead to autoimmunity. Scleroderma, or systemic sclerosis (SSc), offers a unique opportunity to study this relationship since patients with autoantibodies to RNA polymerase III (RPC1) have an increased risk of cancer coincident with SSc onset. Genetic alterations (somatic mutations or loss of heterozygosity, LOH) within the RNA polymerase III locus (protein name RPC1) were identified in cancers from anti-RPC1+ SSc patients and distinct populations of CD4+ T cells were detected that recognized normal and mutated versions of RPC1. Together, these observations suggest that antitumor immunity initiated against the mutated RPC1 protein could cross-react with the wild-type protein and lead to SSc. While CD4+ T cells are critical in orchestrating anti- tumor immune responses, CD8+ T cells are critical for eliminating tumor cells. Moreover, the observed LOH suggests that tumor immunoediting driven by RPC1-specific CD8+ T cells occurred in these patients, and at the same time, there is increasing evidence implicating CD8+ T cells in SSc pathogenesis. An important outstanding question remains: whether RPC1-specific cytotoxic T cells can be identified in patients with SSc and cancer. This proposal seeks to investigate RPC1-specific CD8+ T cells in the peripheral blood and target tissues of patients with SSc and cancer. Aim 1 will examine RPC1-specific CD8+ T cells that are directly involved in both the antitumor response at the site of the cancer as well as in the autoimmune damage of affected skin tissue from SSc patients. In Aim 2, the frequency, phenotype, and effector molecules of RPC1-specific CD8+T-cells will be studied and correlated with cancer status. Finally, Aim 3 will examine the effect of anti-RPC1 autoantibodies on cross-presentation, and potential differences between anti-RPC1+ SSc patients with and without history of cancer. The results of this study will lay the foundation for future studies exploring whether CD8+ T cell responses to RPC1 could be used as targeted monitoring tools and the RPC1 CD8+ T cell epitopes as antigen-specific immunotherapies for SSc, as well as inform the study of other cancer-associated rheumatic diseases. This K08 proposal is designed to promote the career development of the candidate to an independent investigator. To successfully carry out this proposal, she has assembled an outstanding team of mentors, each of whom brings distinct expertise to her project and her scientific development. Moreover, this proposal takes advantage of the rich resources of the Johns Hopkins Scleroderma Center. Building on the candidate’s previous experience studying antigen-specific T cell immunology and antigen processing, this K08 award will enable her to gain additional skills in bioinformatics important for the conduct of translational immunology, develop expertise in the specific niche of autoreactive CD8+ T cells as it pertains to autoimmunity and cancer, and acquire the data and publications necessary to support a strong R01 application.