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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI180278

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

Allison Joy Nielsen,1 Gabriella Kyra Albert,1 Amelia Sanchez,1 Jiangli Chen,1 Jing Liu,1 Andres Sebastian Davalos,1 Degui Geng,1 Xander G. Bradeen,1 Jennifer D. Hintzsche,2 William Robinson,1 Martin McCarter,1 Carol M. Amato,1 Richard Tobin,1 Kasey L. Couts,1 Breelyn Ann Wilky,1 and Eduardo Davila1

1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

Find articles by Nielsen, A. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

Find articles by Davalos, A. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

Find articles by McCarter, M. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

Find articles by Amato, C. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

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1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

Find articles by Wilky, B. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, United States of America

2PherDal Science, Dixon, United States of America

3Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Auror, United States of America

Find articles by Davila, E. in: JCI | PubMed | Google Scholar

Published October 22, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI180278.
Copyright © 2024, Nielsen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 22, 2024 - Version history
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Abstract

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.

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  • Version 1 (October 22, 2024): In-Press Preview
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