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

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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.