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Long-term expression changes of immune-related genes in prostate cancer after radiotherapy

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Abstract

The expression of immune-related genes in cancer cells can alter the anti-tumor immune response and thereby impact patient outcomes. Radiotherapy has been shown to modulate immune-related genes dependent on the fractionation regimen. To identify long-term changes in gene expression after irradiation, PC3 (p53 deleted) and LNCaP (p53 wildtype) prostate cancer cells were irradiated with either a single dose (SD, 10 Gy) or a fractionated regimen (MF) of 10 fractions (1 Gy per fraction). Whole human genome arrays were used to determine gene expression at 24 h and 2 months after irradiation. Immune pathway activation was analyzed with Ingenuity Pathway Analysis software. Additionally, 3D colony formation assays and T-cell cytotoxicity assays were performed. LNCaP had a higher basal expression of immunogenic genes and was more efficiently killed by cytotoxic T-cells compared to PC3. In both cell lines, MF irradiation resulted in an increase in multiple immune-related genes immediately after irradiation, while at 2 months, SD irradiation had a more pronounced effect on radiation-induced gene expression. Both immunogenic and immunosuppressive genes were upregulated in the long term in PC3 cells by a 10 Gy SD irradiation but not in LNCaP. T-cell-mediated cytotoxicity was significantly increased in 10 Gy SD PC3 cells compared to the unirradiated control and could be further enhanced by treatment with immune checkpoint inhibitors. Irradiation impacts the expression of immune-related genes in cancer cells in a fractionation-dependent manner. Understanding and targeting these changes may be a promising strategy for primary prostate cancer and recurrent tumors.

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Acknowledgements

The results shown here are in part based upon data generated by the TCGA Research Network. We would like to thank the TCGA Research Network and the specimen donors. The authors thank Dr. David Cerna (NIH), Dr. Adeola Makinde (NIH), and Dr. Mansoor Ahmed (NIH) for excellent technical assistance.

Funding

This study was supported by the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (grant ZIA BC 010670 to C.N.C) and the NIH Research Program, National Cancer Institute (grant CA197136 to E.G., training grant T32CA121940 to I.E.).

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Authors and Affiliations

  1. Department of Radiation Oncology, Center for Clinical Sciences Research (CCSR), Stanford University School of Medicine, 269 Campus Dr., Room 1260, Stanford, CA, 94305, USA

    Iris Eke, Saravanan Nandagopal, Edward E. Graves & Amato J. Giaccia

  2. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Iris Eke, Molykutty J. Aryankalayil, Michelle A. Bylicky & C. Norman Coleman

  3. Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Veit Sandfort

  4. Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA

    Claire Vanpouille-Box

  5. Oxford Institute of Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX37DQ, UK

    Amato J. Giaccia

  6. Radiation Research Program, National Cancer Institute, National Institutes of Health, Rockville, MD, 20850, USA

    C. Norman Coleman

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  1. Iris Eke
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Contributions

I.E., M.J.A., C.V., and C.N.C. contributed to conceptualization; I.E., M.J.A., S.N., and V.S. contributed to methodology; I.E., M.J.A., M.A.B., and V.S. contributed to investigation; I.E. contributed to writing—original draft; I.E., M.J.A., M.A,B, C.V., E.E.G., and C.N.C. contributed to writing—review and editing; E.E.G. and C.N.C. contributed to funding acquisition; I.E., and C.N.C contributed to supervision.

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Correspondence to Iris Eke.

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Research data and material are stored in an institutional repository and will be shared upon request to the corresponding author. The Cancer Genome Atlas (TCGA) data are available through the Genomic Data Commons Data Portal (https://portal.gdc.cancer.gov/).

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Eke, I., Aryankalayil, M.J., Bylicky, M.A. et al. Long-term expression changes of immune-related genes in prostate cancer after radiotherapy. Cancer Immunol Immunother 71, 839–850 (2022). https://doi.org/10.1007/s00262-021-03036-w

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  • DOI: https://doi.org/10.1007/s00262-021-03036-w

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