Abstract
BackgroundThe manipulation of dendritic cells (DCs) for cancer vaccination has not reached its full potential, despite the revolution in cancer immunotherapy. DCs are fundamental for CD8+ T cell activation, which relies on cross-presentation of exogenous antigen on MHC-I and can be fostered by immunogenic cancer cell death. Translational and clinical research has focused on in vitro-generated monocyte-derived DCs, while the vaccination efficacy of natural conventional type 1 DCs (cDC1s), which are associated with improved anti-tumor immunity and specialize on antigen cross-presentation, remains unknown.MethodsWe isolated primary spleen mouse cDC1s and established a protocol for fast ex vivo activation and antigen-loading with lysates of tumor cells that underwent immunogenic cell death by UV irradiation. Natural tumor antigen-loaded cDC1s were transferred and their potential for induction of endogenous CD8+ and CD4+ T cell responses in vivo, cancer prevention and therapy were assessed in three grafted cancer models. Further, we tested the efficacy of natural cDC1 vaccination in combination and comparison with anti-PD-1 treatment in two “wildtype” tumor models not expressing exogenous antigens.ResultsHerein, we reveal that primary mouse cDC1s ex vivo loaded with dead tumor cell-derived antigen are activated and induce strong CD8+ T cell responses from the endogenous repertoire upon adoptive transfer in vivo through tumor antigen cross-presentation. Notably, cDC1-based vaccines enhance tumor infiltration by cancer-reactive CD8+ and CD4+ T cells and halt progression of engrafted cancer models, including tumors that are refractory to anti-PD-1 treatment. Moreover, combined tumor antigen-loaded primary cDC1 and anti-PD-1 therapy had strong synergistic effects in a PD-1 checkpoint inhibition susceptible cancer model.ConclusionsThis preclinical proof-of-principle study is first to support the therapeutic efficacy of cancer immunotherapy with syngeneic dead tumor cell antigen-loaded mouse cDC1s, the equivalents of the human dendritic cell subset that correlates with beneficial prognosis of cancer patients. Our data pave the way for translation of cDC1-based cancer treatments into the clinic when isolation of natural human cDC1s becomes feasible.
Highlights
The manipulation of dendritic cells (DCs) for cancer vaccination has not reached its full potential, despite the revolution in cancer immunotherapy
To reproduce this situation in our pre-clinical setting while expanding Conventional type 1 DC (cDC1), mice were grafted with B16 melanomas that secrete FMS-like tyrosine kinase 3 ligand (FLT3L) (B16-FLT3L) [34]
Adoptive transfer of natural cDC1s shortly exposed to OVA and poly I:C ex vivo led to increased OT-I proliferation, frequencies in CD8+ T cells and total numbers, as well as augmented IFNγ producing OT-I cells after specific MHC-class I OVA257–264 peptide re-stimulation, as compared with mice transferred with cDC1s pre-treated only with OVA or poly I:C (Fig. 1c-f )
Summary
The manipulation of dendritic cells (DCs) for cancer vaccination has not reached its full potential, despite the revolution in cancer immunotherapy. DCs are fundamental for CD8+ T cell activation, which relies on cross-presentation of exogenous antigen on MHC-I and can be fostered by immunogenic cancer cell death. Translational and clinical research has focused on in vitro-generated monocyte-derived DCs, while the vaccination efficacy of natural conventional type 1 DCs (cDC1s), which are associated with improved anti-tumor immunity and specialize on antigen cross-presentation, remains unknown. The use of DCs for tumor immunotherapy has been limited so far, being the only FDA-approved therapy the blood antigen (Ag)-presenting cell-based vaccine Sipuleucel-T for metastatic castration-resistant prostate cancer [7]. Combination of DC vaccination and immune checkpoint inhibitors appears especially promising, as both target enhanced mobilization and activity of anti-cancer CD8+ T cells [5, 6, 11]. Adoptive transfer of ex vivo-treated DCs to cancer patients demonstrated an excellent safety profile, but the efficacy did not meet the expectations yet [12]
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