Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads
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e2102611118.full.pdf
Description
Published version
Size
1.53 MB
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Checksum (MD5)
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Author(s)
Lussier, Danielle M.
Alspach, Elise
Ward, Jeffrey P.
Miceli, Alexander P.
Runci, Daniele
White, J. Michael
Mpoy, Cedric
Arthur, Cora D.
Kohlmiller, Heather N.
Jacks, Tyler
Date Issued
June 2021
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Version
Final published version
Abstract
Immunotherapies are a promising advance in cancer treatment. However, because only a subset of cancer patients benefits from these treatments it is important to find mechanisms that will broaden the responding patient population. Generally, tumors with high mutational burdens have the potential to express greater numbers of mutant neoantigens. As neoantigens can be targets of protective adaptive immunity, highly mutated tumors are more responsive to immunotherapy. Given that external beam radiation 1) is a standard-of-care cancer therapy, 2) induces expression of mutant proteins and potentially mutant neoantigens in treated cells, and 3) has been shown to synergize clinically with immune checkpoint therapy (ICT), we hypothesized that at least one mechanism of this synergy was the generation of de novo mutant neoantigen targets in irradiated cells. Herein, we use KrasG12D x p53−/− sarcoma cell lines (KP sarcomas) that we and others have shown to be nearly devoid of mutations, are poorly antigenic, are not controlled by ICT, and do not induce a protective antitumor memory response. However, following one in vitro dose of 4- or 9-Gy irradiation, KP sarcoma cells acquire mutational neoantigens and become sensitive to ICT in vivo in a T cell-dependent manner. We further demonstrate that some of the radiation-induced mutations generate cytotoxic CD8+ T cell responses, are protective in a vaccine model, and are sufficient to make the parental KP sarcoma line susceptible to ICT. These results provide a proof of concept that induction of new antigenic targets in irradiated tumor cells represents an additional mechanism explaining the clinical findings of the synergy between radiation and immunotherapy.
MIT Department
Howard Hughes Medical Institute
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1073/pnas.2102611118
