Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells.
Despite the potent ability of dendritic cells (DCs) to stimulate lymphocyte responses and host immunity, granulocyte-macrophage colony-stimulating factor-derived DCs (GM-DCs) used as antitumor vaccines have demonstrated relatively modest success in cancer immunotherapy. We found that injecting GM-DCs into melanoma tumors in mice, or culturing GM-DCs with melanoma-secreted cytokines or melanoma-conditioned medium, rapidly suppressed DC-intrinsic expression of the gene encoding inhibitor of differentiation 2 (ID2), a transcriptional regulator. Melanoma-associated cytokines repressed Id2 transcription in murine DCs through the activation of signal transducer and activator of transcription 3 (STAT3). Enforced expression of ID2 in GM-DCs (ID2-GM-DCs) suppressed their production of the proinflammatory cytokine tumor necrosis factor-α (TNF-α). Vaccination with ID2-GM-DCs slowed the progression of melanoma tumors and enhanced animal survival, which was associated with an increased abundance of tumor-infiltrating interferon-γ-positive CD4(+) effector and CD8(+) cytotoxic T cells and a decreased number of tumor-infiltrating regulatory CD4(+) T cells. The efficacy of the ID2-GM-DC vaccine was improved by combinatorial treatment with a blocking antibody to programmed cell death protein-1 (PD-1), a current immunotherapy that overcomes suppressive immune checkpoint signaling. Collectively, our data reveal a previously unrecognized STAT3-mediated immunosuppressive mechanism in DCs and indicate that DC-intrinsic ID2 promotes tumor immunity by modulating tumor-associated CD4(+) T cell responses. Thus, inhibiting STAT3 or overexpressing ID2 selectively in DCs may improve the efficiency of DC vaccines in cancer therapy.
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Haiyan S
HS
Li
Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chengwen
C
Liu
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yichuan
Y
Xiao
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Fuliang
F
Chu
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Xiaoxuan
X
Liang
Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Weiyi
W
Peng
Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jianhua
J
Hu
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sattva S
SS
Neelapu
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Shao-Cong
SC
Sun
Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Patrick
P
Hwu
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. swatowic@mdanderson.org.
Stephanie S
SS
Watowich
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D007111:Immunity, Cellular; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000276:immunology*; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D019496:Cancer Vaccines; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
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