A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice
Antigen-encoding, lipoplex-formulated RNA (RNA-LPX) enables systemic delivery to lymphoid compartments and selective expression in resident antigen-presenting cells. We report here that the rejection of CT26 tumors, mediated by local radiotherapy (LRT), is further augmented in a CD8+ T cell-dependen...
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doaj-3e5a60314c6a4287a58876c10a7472b02021-09-24T14:41:24ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2020.17719251771925A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in miceNadja Salomon0Fulvia Vascotto1Abderaouf Selmi2Mathias Vormehr3Juliane Quinkhardt4Thomas Bukur5Barbara Schrörs6Martin Löewer7Mustafa Diken8Özlem Türeci9Ugur Sahin10Sebastian Kreiter11TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHTRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHTRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHBioNTech SEBioNTech SETRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHTRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHTRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHTRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHBioNTech SEBioNTech SETRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbHAntigen-encoding, lipoplex-formulated RNA (RNA-LPX) enables systemic delivery to lymphoid compartments and selective expression in resident antigen-presenting cells. We report here that the rejection of CT26 tumors, mediated by local radiotherapy (LRT), is further augmented in a CD8+ T cell-dependent manner by an RNA-LPX vaccine that encodes CD4+ T cell-recognized neoantigens (CD4 neoantigen vaccine). Whereas CD8+ T cells induced by LRT alone were primarily directed against the immunodominant gp70 antigen, mice treated with LRT plus the CD4 neoantigen vaccine rejected gp70-negative tumors and were protected from rechallenge with these tumors, indicating a potent poly-antigenic CD8+ T cell response and T cell memory. In the spleens of CD4 neoantigen-vaccinated mice, we found a high number of activated, poly-functional, Th1-like CD4+ T cells against ME1, the immunodominant CD4 neoantigen within the poly-neoantigen vaccine. LRT itself strongly increased CD8+ T cell numbers and clonal expansion. However, tumor infiltrates of mice treated with CD4 neoantigen vaccine/LRT, as compared to LRT alone, displayed a higher fraction of activated gp70-specific CD8+ T cells, lower PD-1/LAG-3 expression and contained ME1-specific IFNγ+ CD4+ T cells capable of providing cognate help. CD4 neoantigen vaccine/LRT treatment followed by anti-CTLA-4 antibody therapy further enhanced the efficacy with complete remission of gp70-negative CT26 tumors and survival of all mice. Our data highlight the power of combining synergistic modes of action and warrants further exploration of the presented treatment schema.http://dx.doi.org/10.1080/2162402X.2020.1771925radiotherapycancer vaccinesneoantigenscd4+ t cellsrna-lpx |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nadja Salomon Fulvia Vascotto Abderaouf Selmi Mathias Vormehr Juliane Quinkhardt Thomas Bukur Barbara Schrörs Martin Löewer Mustafa Diken Özlem Türeci Ugur Sahin Sebastian Kreiter |
spellingShingle |
Nadja Salomon Fulvia Vascotto Abderaouf Selmi Mathias Vormehr Juliane Quinkhardt Thomas Bukur Barbara Schrörs Martin Löewer Mustafa Diken Özlem Türeci Ugur Sahin Sebastian Kreiter A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice OncoImmunology radiotherapy cancer vaccines neoantigens cd4+ t cells rna-lpx |
author_facet |
Nadja Salomon Fulvia Vascotto Abderaouf Selmi Mathias Vormehr Juliane Quinkhardt Thomas Bukur Barbara Schrörs Martin Löewer Mustafa Diken Özlem Türeci Ugur Sahin Sebastian Kreiter |
author_sort |
Nadja Salomon |
title |
A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice |
title_short |
A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice |
title_full |
A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice |
title_fullStr |
A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice |
title_full_unstemmed |
A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice |
title_sort |
liposomal rna vaccine inducing neoantigen-specific cd4+ t cells augments the antitumor activity of local radiotherapy in mice |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2020-01-01 |
description |
Antigen-encoding, lipoplex-formulated RNA (RNA-LPX) enables systemic delivery to lymphoid compartments and selective expression in resident antigen-presenting cells. We report here that the rejection of CT26 tumors, mediated by local radiotherapy (LRT), is further augmented in a CD8+ T cell-dependent manner by an RNA-LPX vaccine that encodes CD4+ T cell-recognized neoantigens (CD4 neoantigen vaccine). Whereas CD8+ T cells induced by LRT alone were primarily directed against the immunodominant gp70 antigen, mice treated with LRT plus the CD4 neoantigen vaccine rejected gp70-negative tumors and were protected from rechallenge with these tumors, indicating a potent poly-antigenic CD8+ T cell response and T cell memory. In the spleens of CD4 neoantigen-vaccinated mice, we found a high number of activated, poly-functional, Th1-like CD4+ T cells against ME1, the immunodominant CD4 neoantigen within the poly-neoantigen vaccine. LRT itself strongly increased CD8+ T cell numbers and clonal expansion. However, tumor infiltrates of mice treated with CD4 neoantigen vaccine/LRT, as compared to LRT alone, displayed a higher fraction of activated gp70-specific CD8+ T cells, lower PD-1/LAG-3 expression and contained ME1-specific IFNγ+ CD4+ T cells capable of providing cognate help. CD4 neoantigen vaccine/LRT treatment followed by anti-CTLA-4 antibody therapy further enhanced the efficacy with complete remission of gp70-negative CT26 tumors and survival of all mice. Our data highlight the power of combining synergistic modes of action and warrants further exploration of the presented treatment schema. |
topic |
radiotherapy cancer vaccines neoantigens cd4+ t cells rna-lpx |
url |
http://dx.doi.org/10.1080/2162402X.2020.1771925 |
work_keys_str_mv |
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