1. A liposomal RNA vaccine inducing neoantigen-specific CD4 + T cells augments the antitumor activity of local radiotherapy in mice.
- Author
-
Salomon N, Vascotto F, Selmi A, Vormehr M, Quinkhardt J, Bukur T, Schrörs B, Löewer M, Diken M, Türeci Ö, Sahin U, and Kreiter S
- Subjects
- Animals, Antigens, Neoplasm genetics, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Female, Mice, Mice, Inbred BALB C, RNA, Cancer Vaccines
- 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., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2020
- Full Text
- View/download PDF