Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0565-5) contains supplementary material, which is available to authorized users.

Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103+conventional dendritic cells

“…10 11 Moreover, purified murine lymphoid organ cDC1s demonstrated effective tumor control. 20 The number of naturally occurring DCs that can be harvested for clinical use is limited, however, posing challenges for effective translation. 39 40 In mice, this hurdle was overcome by generating abundant amounts of CD103 + cDC1s in culture 29 ; BM cells from one mouse can generate sufficient quantities of CD103 + cDC1s for vaccination of 30-50 tumor-bearing animals.…”

“…Our work and studies by others suggest that multiple routes of cDC1 vaccine delivery are effective. A prior study used intradermal delivery of lymphoid organ CD8α + cDC1s loaded with dead tumor cell-derived antigens, 20 while we employed i.t. as well as i.v.…”

TSHZ3 is A Prognostic Biomarker with Immune Infiltration in Stomach Adenocarcinoma and Bladder Urothelial Carcinoma

“…pDCs, present the phenotypes as CD303(CLEC4C), CD304(NRP1), CD123(IL3RA), CCR2 and CXCR3, which predict poor prognosis of cancers by promoting the expansion of Treg cell populations [12,41]. cDC1s, present the phenotypes as HLA-DR, CD141, XCR1, CLEC9A and DEC-205(LY75), are often related to superior crosspresentation of antigens, which results in stronger CD8 + T cell immunity, and can additionally support Th1 cell polarization of CD4 + T cells [42][43][44][45][46]. These findings support our findings that pDCs infiltration has positive correlation with TSHZ3 expression level in STAD and BLCA.…”

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

“…The therapeutic immunization limited the tumor growth in three different mouse cancer models, two of which do not express exogenous or dominant antigens. Tumor cell lysate-loaded cDC1 administration significantly increased the efficacy of anti-PD-1 therapy in both immune checkpoint antibody sensitive and resistant models [171].…”