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

Award Number: K08AR077732
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/03/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	11/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $158,729 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	9/11/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$158,729
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	9/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	9/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $158,729

Issue Date FY: 2024 ( Subtotal = $158,729 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/26/2024	NON-COMPETING CONTINUATION	$158,729
														Subtotal = $158,729

Issue Date FY: 2023 ( Subtotal = $158,729 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	9/11/2023	NON-COMPETING CONTINUATION	$158,729
2023	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $158,729

Issue Date FY: 2022 ( Subtotal = $158,729 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/7/2022	NON-COMPETING CONTINUATION	$158,729
														Subtotal = $158,729

Issue Date FY: 2021 ( Subtotal = $158,729 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/1/2021	NEW	$158,729
														Subtotal = $158,729

Grand Total All Awards = $793,645

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

Award Number: K08AR077732

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/03/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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