Background/Purpose: Increasing evidence suggests an immunologic link between cancer and autoimmunity. Systemic sclerosis (SSc), offers a unique opportunity to study the evolution of naturally occurring anti-cancer immune responses to autoimmunity 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 (POLR3A) locus were identified in cancers from anti-RPC1+ SSc patients and distinct populations of CD4+ T cells that recognized normal and mutated versions of RPC1 were detected in these patients. The observed LOH suggests that tumor immunoediting driven by RPC1-specific CD8+ T cells, critical in eliminating cancer cells, could have occurred in these patients. This possibility combined with increasing evidence implicating CD8+ T cells in SSc pathogenesis leads to an important outstanding question: do RPC1-specific cytotoxic T cells exist in patients with SSc and cancer?

Methods: Patients with a diagnosis of SSc, history of concomitant cancer (interval -0.3-1.5 years), and anti-RPC1 antibodies were recruited from the Johns Hopkins Scleroderma Center. Peripheral blood mononuclear cells and excess cancer tissue from clinically obtained biopsies/surgeries were studied. Research skin biopsies were performed in consenting participants. We performed T-cell receptor (TCR) sequencing on CD8+ T cells in 5 patients, which were expanded in response to RPC1 peptides and searched for the RPC1-specific CDR3 sequences (i.e., clonotypes) in their corresponding cancer tissues (n=5) and skin tissue (n=1) if available.

Results: We identified a sum of 13 to 139 separate TCRs of CD8+ T cells per patient that expanded after stimulation with 25 distinct RPC1 peptides, even when SSc was not active at the time of blood sampling. Each patient had 1-13 clonotypes per peptide (median 1) against 9-21 RPC1 epitopes per patient (median 16) at cumulative frequency 0.83-5.75% RPC1-reactive TCRs per patient (median 2.15%) (Figure 1a, b). We subsequently identified RPC1-reactive CD8+ T cell clonotypes in the cancer tissue of 4 out of the 5 patients, with the difference between cancer diagnosis and blood sampling in the patients with cancer-infiltrating cells ranging between 0-6 years. The remaining patient (RPC1-5) without detectable RPC1-reactive clonotypes in their cancer tissue had a lag time of 16 years between cancer diagnosis and blood sampling. In the patient with available skin tissue (RPC1-2), a highly abundant RPC1-reactive CD8+ T cell clonotype was also identified, which comprised 16% of all the T cells present in the skin biopsy (Figure 1c).

Conclusion: This study is the first report of RPC1-reactive CD8+ T cells in SSc and the first to demonstrate that these antigen-specific cells can be found in the cancer and skin tissue of patients with anti-RPC1+ SSc. Taken together, this supports the hypothesis that the anti-RPC1 immune response developed during active cancer immunosurveillance diversifies to recognize wild-type RPC1 epitopes, contributing to SSc pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rna-polymerase-iii-specific-cd8-t-cells-at-the-interface-between-scleroderma-and-cancer/