Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads
<jats:p>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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/135643 |
| _version_ | 1826205116426878976 |
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| author | 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 Artyomov, Maxim N Rogers, Buck E Schreiber, Robert D |
| author_facet | 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 Artyomov, Maxim N Rogers, Buck E Schreiber, Robert D |
| author_sort | Lussier, Danielle M |
| collection | MIT |
| description | <jats:p>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 Kras<jats:sup>G12D</jats:sup> x p53<jats:sup>−/−</jats:sup> 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<jats:sup>+</jats:sup> 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.</jats:p> |
| first_indexed | 2024-09-23T13:07:19Z |
| format | Article |
| id | mit-1721.1/135643 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:07:19Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1356432021-12-12T03:58:26Z Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads 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 Artyomov, Maxim N Rogers, Buck E Schreiber, Robert D <jats:p>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 Kras<jats:sup>G12D</jats:sup> x p53<jats:sup>−/−</jats:sup> 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<jats:sup>+</jats:sup> 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.</jats:p> 2021-10-27T20:24:24Z 2021-10-27T20:24:24Z 2021 2021-07-16T18:33:28Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135643 en 10.1073/pnas.2102611118 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | 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 Artyomov, Maxim N Rogers, Buck E Schreiber, Robert D Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads |
| title | Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads |
| title_full | Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads |
| title_fullStr | Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads |
| title_full_unstemmed | Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads |
| title_short | Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads |
| title_sort | radiation induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads |
| url | https://hdl.handle.net/1721.1/135643 |
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