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

项目概要/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，在健康人中识别自身抗原是不可能的。 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（RPC 1）自身抗体的患者 与SSc发作同时发生的癌症。遗传改变（体细胞突变或杂合性缺失，洛） 在RNA聚合酶III基因座（蛋白质名称RPC 1）内， 检测到患者和不同的CD 4 + T细胞群体，其识别正常和突变形式的 RPC 1.总之，这些观察结果表明，针对突变的RPC 1蛋白的抗肿瘤免疫启动 可以与野生型蛋白交叉反应并导致SSc。虽然CD 4 + T细胞在协调抗- 在肿瘤免疫应答中，CD 8 + T细胞对于消除肿瘤细胞至关重要。此外，观察到的洛 提示在这些患者中发生了由RPC 1特异性CD 8 + T细胞驱动的肿瘤免疫编辑，并且在这些患者中， 同时，越来越多的证据表明，CD 8 + T细胞参与了SSc的发病机制。一个重要的杰出 问题仍然存在：是否RPC 1特异性细胞毒性T细胞可以在SSc和癌症患者中鉴定。 该提案旨在研究RPC 1特异性CD 8 + T细胞在外周血和靶组织中的作用。 SSc和癌症患者。目的1将检测直接参与两种免疫反应的RPC 1特异性CD 8 + T细胞。 癌症部位的抗肿瘤反应以及受影响皮肤组织的自身免疫损伤 SSc患者在目标2中，RPC 1特异性CD 8 + T细胞的频率、表型和效应分子 将被研究并与癌症状态相关联。最后，目标3将检查抗RPC 1的效果 交叉呈递的自身抗体，以及抗RPC 1 + SSc患者与 没有癌症史本研究的结果将为今后的研究奠定基础，探讨是否 CD 8 + T细胞对RPC 1的应答可用作靶向监测工具，RPC 1的CD 8 + T细胞表位 作为SSc的抗原特异性免疫疗法，并为其他癌症相关风湿性关节炎的研究提供信息。 疾病此K 08提案旨在促进候选人的职业发展， 调查员为了成功实施这一计划，她组建了一支优秀的导师团队， 他们为她的项目和科学发展带来了独特的专业知识。此外，该提案将 约翰霍普金斯硬皮病中心的丰富资源优势。根据候选人之前的 研究抗原特异性T细胞免疫学和抗原加工的经验，这个K 08奖将使她 获得生物信息学的额外技能，这对翻译免疫学的开展很重要， 在自身反应性CD 8 + T细胞的特定生态位中，因为它涉及自身免疫和癌症，并获得数据 和出版物，以支持一个强大的R 01应用程序。

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.