Dataset Information

Immunotherapy with Dendritic Cells Modified with Tumor-Associated Antigen Gene Demonstrates Enhanced Antitumor Effect Against Lung Cancer.

ABSTRACT:

Background

Immunotherapy using dendritic cell (DC) vaccine has the potential to overcome the bottleneck of cancer therapy.

Methods

We engineered Lewis lung cancer cells (LLCs) and bone marrow-derived DCs to express tumor-associated antigen (TAA) ovalbumin (OVA) via lentiviral vector plasmid encoding OVA gene. We then tested the antitumor effect of modified DCs both in vitro and in vivo.

Results

The results demonstrated that in vitro modified DCs could dramatically enhance T-cell proliferation (P<.01) and killing of LLCs than control groups (P<.05). Moreover, modified DCs could reduce tumor size and prolong the survival of LLC tumor-bearing mice than control groups (P<.01 and P<.01, respectively). Mechanistically, modified DCs demonstrated enhanced homing to T-cell-rich compartments and triggered more naive T cells to become cytotoxic T lymphocytes, which exhibited significant infiltration into the tumors. Interestingly, modified DCs also markedly reduced tumor cells harboring stem cell markers in mice (P<.05), suggesting the potential role on cancer stem-like cells.

Conclusion

These findings suggested that DCs bioengineered with TAA could enhance antitumor effect and therefore represent a novel anticancer strategy that is worth further exploration.

SUBMITTER: Jiang T

PROVIDER: S-EPMC5266489 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

Immunotherapy with Dendritic Cells Modified with Tumor-Associated Antigen Gene Demonstrates Enhanced Antitumor Effect Against Lung Cancer.

Jiang Tao T Chen Xiao X Zhou Wei W Fan Guoxin G Zhao Peilin P Ren Shengxiang S Zhou Caicun C Zhang Jun J

Translational oncology 20170125 2

<h4>Background</h4>Immunotherapy using dendritic cell (DC) vaccine has the potential to overcome the bottleneck of cancer therapy.<h4>Methods</h4>We engineered Lewis lung cancer cells (LLCs) and bone marrow-derived DCs to express tumor-associated antigen (TAA) ovalbumin (OVA) via lentiviral vector plasmid encoding OVA gene. We then tested the antitumor effect of modified DCs both in vitro and in vivo.<h4>Results</h4>The results demonstrated that in vitro modified DCs could dramatically enhance T ...[more]

PMID: 28129580

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Project description: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.

Dataset Information

Immunotherapy with Dendritic Cells Modified with Tumor-Associated Antigen Gene Demonstrates Enhanced Antitumor Effect Against Lung Cancer.

Background

Methods

Results

Conclusion

Publications

Immunotherapy with Dendritic Cells Modified with Tumor-Associated Antigen Gene Demonstrates Enhanced Antitumor Effect Against Lung Cancer.

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