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Radiation-associated secondary malignancies: a novel opportunity for applying immunotherapies

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Abstract

Radiation is commonly used as a treatment intended to cure or palliate cancer patients. Despite remarkable advances in the precision of radiotherapy delivery, even the most advanced forms inevitably expose some healthy tissues surrounding the target site to radiation. On rare occasions, this results in the development of radiation-associated secondary malignancies (RASM). RASM are typically high-grade and carry a poorer prognosis than their non-radiated counterparts. RASM are characterized by a high mutation burden, increased T cell infiltration, and a microenvironment that bears unique inflammatory signatures of prior radiation, including increased expression of various cytokines (e.g., TGF-β, TNF-α, IL4, and IL10). Interestingly, these cytokines have been shown to up-regulate the expression of PD-1 and/or PD-L1—an immune checkpoint receptor/ligand pair that is commonly targeted by immune checkpoint blocking immunotherapies. Here, we review the current understanding of the tumor-immune interactions in RASM, highlight the distinct clinical and molecular characteristics of RASM that may render them immunologically “hot,” and propose a rationale for the formal testing of immune checkpoint blockade as a treatment approach for patients with RASM.

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  1. Tavus Atajanova and Md Mahfuzur Rahman have contributed equally.

Authors and Affiliations

  1. Biochemistry and Biophysics Program, Amherst College, Amherst, MA, 01002, USA

    Tavus Atajanova

  2. Department of Sociology, Amherst College, Amherst, MA, 01002, USA

    Tavus Atajanova

  3. Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, 53726, USA

    Tavus Atajanova, Md Mahfuzur Rahman & Zachary S. Morris

  4. Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA

    David J. Konieczkowski

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T.A., M.R., D.K. and Z.M. conceptualize and wrote the main manuscript text. All authors reviewed the manuscript.

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Correspondence to Zachary S. Morris.

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Z. Morris declares that he is on the Scientific Advisory Board for Archeus Technologies and for Seneca Therapeutics. No disclosures were reported by the other authors.

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Atajanova, T., Rahman, M.M., Konieczkowski, D.J. et al. Radiation-associated secondary malignancies: a novel opportunity for applying immunotherapies. Cancer Immunol Immunother 72, 3445–3452 (2023). https://doi.org/10.1007/s00262-023-03532-1

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  • DOI: https://doi.org/10.1007/s00262-023-03532-1

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