Abstract
BackgroundCD8+ T cell-mediated adaptive cellular immunity and natural killer (NK) cell-mediated innate immunity both play important roles in tumour immunity. This study aimed to develop therapeutic tumour vaccines based on double-activation of CD8+ T and NK cells.MethodsThe immune Epitope database, Molecular Operating Environment software, and enzyme-linked immunosorbent assay were used for epitope identification. Flow cytometry, confocal microscopy, UPLC-QTOF-MS, and RNA-seq were utilized for evaluating immunity of PBMC-derived DCs, CD8+ T or NK cells and related pathways. HLA-A2.1 transgenic mice combined with immunologically reconstituted tumour-bearing mice were used to examine the antitumour effect and safety of epitope vaccines.ResultsWe identified novel HLA-A2.1-restricted extracellular matrix protein 1(ECM1)-derived immunodominant epitopes in which LA induced a potent immune response. We also found that LA-loaded DCs upregulated the frequency of CD3+/CD8+ T cells, CD45RO+/CD69+ activated memory T cells, and CD3−/CD16+/CD56+ NK cells. We demonstrated cytotoxic granule release of LA/DC-CTLs or LA/DC-NK cells and cytotoxicity against tumour cells and microtissue blocks via the predominant IFN-γ/perforin/granzyme B cell death pathway. Further investigating the mechanism of LA-mediated CD8+ T activation, we found that LA could be internalized into DCs through phagocytosis and then formed a LA-MHC-I complex presented onto the DC surface for recognition of the T cell receptor to upregulate Zap70 phosphorylation levels to further activate CD8+ T cells by DC-CTL interactions. In addition, LA-mediated DC-NK crosstalk through stimulation of the TLR4-p38 MAPK pathway increased MICA/B expression on DCs to interact with NKG2D for NK activation. Promisingly, LA could activate CD8+ T cells and NK cells simultaneously via interacting with DCs to suppress tumours in vivo. Moreover, the safety of LA was confirmed.ConclusionsLA-induced immune antitumour activity through DC cross-activation with CD8+ T and NK cells, which demonstrated proof-of-concept evidence for the capability and safety of a novel therapeutic tumour vaccine.
Highlights
CD8+ T cell-mediated adaptive cellular immunity and natural killer (NK) cell-mediated innate immunity both play important roles in tumour immunity
Yu et al J Hematol Oncol (2021) 14:71 mechanism of LA-mediated CD8+ T activation, we found that LA could be internalized into Dendritic cell (DC) through phagocytosis and formed a LA-Major histocompatibility complex class I (MHC-I) complex presented onto the DC surface for recognition of the T cell receptor to upregulate Zap70 phosphorylation levels to further activate CD8+ T cells by DC-Cytotoxic T lymphocyte (CTL) interactions
LA-mediated DC-NK crosstalk through stimulation of the Toll-like receptor 4 (TLR4)-p38 mitogen-activated protein kinase (MAPK) pathway increased major histocompatibility complex (MHC) class I chain-related A/B (MICA/B) expression on DCs to interact with natural killer group 2 member D (NKG2D) for NK activation
Summary
CD8+ T cell-mediated adaptive cellular immunity and natural killer (NK) cell-mediated innate immunity both play important roles in tumour immunity. This study aimed to develop therapeutic tumour vaccines based on double-activation of CD8+ T and NK cells. Developing therapeutic tumour vaccines, especially through combination of the adaptive immune response of CD8+ T cells and innate immune response of NK cells to exert targeted antitumour effects is a promising strategy [5, 6]. We identified novel ECM1-derived HLA-A2.1 CTL epitopes and found LA and YL with potent DC (dendritic cell)-CTL antitumour effects. We further conducted RNA-sequencing (RNA-seq)based transcriptome analysis, and mouse model (xenograft mouse models and a allograft tumour-bearing HLA-A2.1 Tg mouse model)-based effect verification to identify mechanism of double-activation with DCCTLs and DC-NK cells against tumours, which paved the way for the development of novel therapeutic tumour vaccines
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