Research ArticleCancer Immunology

Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells

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Science Signaling  27 Sep 2016:
Vol. 9, Issue 447, pp. ra94
DOI: 10.1126/scisignal.aaf3957

Engineering antitumor activity

Dendritic cells are critical mediators of the immune response to infection. Despite their potential, antitumor vaccines based on injecting dendritic cells have not been effective. Using mouse models of melanoma, Li et al. found that tumor cells release cytokines that suppress the ability of tumor-infiltrating dendritic cells to mount an antitumor response. The cytokines released from melanoma cells activated the transcription factor STAT3, which repressed the expression of the gene encoding the transcription regulator ID2. Constitutively expressing ID2 dampened production of proinflammatory cytokines in dendritic cells and promoted dendritic cell–mediated immunostimulatory lymphocyte responses. Vaccination experiments in tumor-bearing mice suggested that engineering dendritic cells to overcome or prevent the tumor-derived cytokine response in the injected dendritic cells, by either deleting STAT3 or overexpressing ID2, might prove an effective immunotherapy strategy in cancer patients.


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.

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