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A liposomal RNA vaccine inducing neoantigen-specific CD4⁺ T cells augments the antitumor activity of local radiotherapy in mice.

ABSTRACT: 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.

SUBMITTER: Salomon N

PROVIDER: S-EPMC7458669 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice.

Salomon Nadja N Vascotto Fulvia F Selmi Abderaouf A Vormehr Mathias M Quinkhardt Juliane J Bukur Thomas T Schrörs Barbara B Löewer Martin M Diken Mustafa M Türeci Özlem Ö Sahin Ugur U Kreiter Sebastian S

Oncoimmunology 20200622 1

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 direc ...[more]

PMID: 32923128

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Project description:BackgroundNeoantigens are promising immunogens for cancer vaccines and are often delivered as adjuvanted peptide vaccines. Adenoviral (Ad) vectors have been shown to induce strong CD8+ T cell responses as vaccines against SARS-CoV-2, Ebola, and Zika, but their utility as neoantigen delivery vectors remains largely unexplored. In this study, we examine how an Ad-vectored neoantigen vaccine would impact tumor immunity compared with a peptide neoantigen vaccine.MethodsWe generated Ad serotype 26 (Ad26) vaccine candidates encoding B16-F10-ovalbumin (OVA) and MC38-specific neoantigens. Ad26 vaccines were compared with adjuvanted peptide delivery as prophylactic vaccines in B16-F10-OVA and MC38 challenge models. Immune responses induced by the best Ad26 vaccine (Ad26.VP22.7Epi) were compared with peptide vaccination systemically and within the tumor. Following vaccination with Ad26.VP22.7Epi, peptide, or sham, tumor-infiltrating CD45+ cells were analyzed using single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) to identify vaccine-induced differences in the tumor microenvironment.ResultsSingle-shot Ad26 vaccines induced greater neoantigen-specific interferon-γ CD8+ T cell immune responses than two-shot adjuvanted peptide vaccines in mice, and Ad26.VP22.7Epi also provided superior protective efficacy compared with the peptide vaccine following tumor challenge. Ad26.VP22.7Epi induced a robust immunodominant CD8+ T cell response against the Adpgk neoantigen, while the peptide vaccine-induced lower responses against both Adpgk and Reps1 neoantigens. scRNA-seq analysis of CD45+ tumor-infiltrating cells demonstrated that both Ad26.VP22.7Epi and peptide vaccine-induced similar numbers of infiltrating CD8+ T cells. However, Ad26.VP22.7Epi induced CD8+ T cells showed more upregulation of T cell maturation, activation, and Th1 pathways compared with peptide vaccine induced CD8+ T cells, suggesting improved functional T cell quality. TCR-seq of these tumor-infiltrating lymphocytes also demonstrated that Ad26.VP22.7Epi generated larger T cell hyperexpanded clones compared with the peptide vaccine.ConclusionsThese results suggest that the Ad26.VP22.7Epi vaccine led to improved tumor control compared with the peptide vaccine due to increased T cell hyperexpansion and functional activation. Our data suggest that future cancer vaccine development strategies should focus on inducing functional hyperexpanded CD8+ T cell responses and not only maximizing tumor infiltrating CD8+ T cell numbers.

Project description:BackgroundAntitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy.MethodsThe impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans.ResultsPrior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy.ConclusionPre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

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A liposomal RNA vaccine inducing neoantigen-specific CD4⁺ T cells augments the antitumor activity of local radiotherapy in mice.

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A liposomal RNA vaccine inducing neoantigen-specific CD4<sup>+</sup> T cells augments the antitumor activity of local radiotherapy in mice.

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