RT Journal Article
SR Electronic
T1 Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 100
DO 10.1186/s40425-019-0565-5
VO 7
IS 1
A1 Stefanie K. Wculek
A1 Joaquín Amores-Iniesta
A1 Ruth Conde-Garrosa
A1 Sofía C. Khouili
A1 Ignacio Melero
A1 David Sancho
YR 2019
UL http://jitc.bmj.com/content/7/1/100.abstract
AB Background 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.Methods We 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.Results Herein, 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.Conclusions This 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.Abbreviations:AgAntigenB16-FLT3LFLT3L-expressing B16 melanoma cellsB16-OVAOVA-expressing B16 melanoma cellsCD8+ CTLsCytotoxic CD8+ T lymphocytescDC1Conventional type 1 DCcDC2Conventional type 2 DCDCDendritic cellFLT3LFMS-like tyrosine kinase 3 ligandGMPGood manufacturing practiceH-2Kbm1 miceC57BL/6H2Kbm1 miceHMGB1High-mobility group box protein 1ICDImmunogenic cell deathIDIntradermaliLNInguinal LNIPIntraperitonealISQAVHAAHAEINEAGROVA323–339 peptideIVIntravenousLNLymph nodemoDCsMonocyte-derived DCso/nOvernightOVAOvalbuminpDCPlasmacytoid DCSIINFEKLOVA257–264 peptideTCLTumor cell lysatetdLNTumor-draining iLNTLR3Toll-like receptor 3UVUltraviolet