DNA-PK inhibition enhances neoantigen diversity and increases T cell responses to immunoresistant tumors.

Autor:	Nielsen AJ; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Albert GK; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Sanchez A; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Chen J; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Liu J; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Davalos AS; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Geng D; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Bradeen XG; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Hintzsche JD; PherDal Science, Dixon, United States of America., Robinson W; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., McCarter M; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Amato CM; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Tobin R; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Couts KL; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Wilky BA; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America., Davila E; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Oct 22. Date of Electronic Publication: 2024 Oct 22.
DOI:	10.1172/JCI180278
Abstrakt:	Effective antitumor T cell activity relies on the expression and MHC presentation of tumor neoantigens. Tumor cells can evade T cell detection by silencing the transcription of antigens or by altering MHC machinery resulting in inadequate neoantigen-specific T cell activation. We identified DNA-PK inhibitor (DNA-PKi) NU7441 as a promising immunomodulator that reduced immunosuppressive proteins while increasing MHC-I expression in a panel of human melanoma cell lines. In tumor-bearing mice, combination therapy using NU7441 and immune adjuvants STING ligand and CD40 agonist (NU-SL40) substantially increased and diversified the neoantigen landscape, antigen presenting machinery, and consequently substantially increased both the number and repertoire of neoantigen-reactive tumor infiltrating lymphocytes (TILs). DNA-PK-inhibition or knockout promoted transcription and protein expression of various neoantigens in human and mouse melanomas and induced sensitivity to ICB in resistant tumors. In patients, PRKDC levels inversely correlated with MHC I expression and CD8 TILs but positively correlated with increased neoantigen loads and improved responses to ICB. These studies suggest that inhibiting DNA-PK activity can restore tumor immunogenicity by increasing neoantigen expression and presentation and broadening the neoantigen-reactive T cell population.
Databáze:	MEDLINE
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