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

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2022 · $158,729

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10478930
- **Project number:** 5K08AR077732-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Eleni Tiniakou
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $158,729
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478930

## Citation

> US National Institutes of Health, RePORTER application 10478930, RNA Polymerase III specific CD8+ T cells: a mechanistic insight into cancer-induced autoimmunity in scleroderma (5K08AR077732-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10478930. Licensed CC0.

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