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Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control
Claire Lhuillier, … , Silvia C. Formenti, Sandra Demaria
Claire Lhuillier, … , Silvia C. Formenti, Sandra Demaria
Published January 21, 2021
Citation Information: J Clin Invest. 2021;131(5):e138740. https://doi.org/10.1172/JCI138740.
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Research Article Immunology Oncology Article has an altmetric score of 38

Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control

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Abstract

Neoantigens generated by somatic nonsynonymous mutations are key targets of tumor-specific T cells, but only a small number of mutations predicted to be immunogenic are presented by MHC molecules on cancer cells. Vaccination studies in mice and patients have shown that the majority of neoepitopes that elicit T cell responses fail to induce significant antitumor activity, for incompletely understood reasons. We report that radiotherapy upregulates the expression of genes containing immunogenic mutations in a poorly immunogenic mouse model of triple-negative breast cancer. Vaccination with neoepitopes encoded by these genes elicited CD8+ and CD4+ T cells that, whereas ineffective in preventing tumor growth, improved the therapeutic efficacy of radiotherapy. Mechanistically, neoantigen-specific CD8+ T cells preferentially killed irradiated tumor cells. Neoantigen-specific CD4+ T cells were required for the therapeutic efficacy of vaccination and acted by producing Th1 cytokines, killing irradiated tumor cells, and promoting epitope spread. Such a cytotoxic activity relied on the ability of radiation to upregulate class II MHC molecules as well as the death receptors FAS/CD95 and DR5 on the surface of tumor cells. These results provide proof-of-principle evidence that radiotherapy works in concert with neoantigen vaccination to improve tumor control.

Authors

Claire Lhuillier, Nils-Petter Rudqvist, Takahiro Yamazaki, Tuo Zhang, Maud Charpentier, Lorenzo Galluzzi, Noah Dephoure, Cristina C. Clement, Laura Santambrogio, Xi Kathy Zhou, Silvia C. Formenti, Sandra Demaria

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Figure 8

Both CD4+ and CD8+ neoantigen-specific T cells are required for the antitumor activity of the vaccine.

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Both CD4+ and CD8+ neoantigen-specific T cells are required for the anti...
(A) Mice were vaccinated weekly with adjuvant alone (RT), all 3 neoepitopes (Neo-vax), or only 2 neoepitopes (CAND1/DHX58) starting 2 weeks before 4T1 cell inoculation. Tumors were irradiated with a dose of 8 Gy on days 12, 13, and 14. Tumor volume over time; *P < 0.05, with repeated-measures 2-way ANOVA (n = 8–9 mice per group). (B) Secreted IFN-γ was measured in the supernatant of tumor-draining lymph node cells harvested on day 31 and stimulated 48 hours with indicated peptides (CAND1, DHX58, ADGRF5-II, and AH1-A5). **P < 0.01, ***P < 0.001, with Kruskal-Wallis and Dunn’s multiple-comparison tests (n = 8). (C) In vitro killing of untreated or irradiated 4T1 target cells (as described in Figure 3E) using as effectors splenocytes harvested on day 31 and restimulated for 6 days with CAND1 or ADGRF5-II, followed by CD8+ or CD4+ T cell isolation, respectively. Ratios of untreated to irradiated cells were calculated as described in Methods. *P < 0.05, ***P < 0.001, with unpaired 2-tailed Student’s t test (n = 7). (D) Tumor volume over time of mice (n = 7–8 per group) treated as in A with adjuvant alone (RT) or with Neo-vax and RT. Some mice received CD4- or CD8-depleting antibodies starting 2 days before RT and maintained weekly; *P < 0.05, **P < 0.01, with repeated-measures 2-way ANOVA. All data presented are expressed as mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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