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Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves
the antitumor efficacy of dendritic cells
#MMPMID27678219
Li HS
; Liu C
; Xiao Y
; Chu F
; Liang X
; Peng W
; Hu J
; Neelapu SS
; Sun SC
; Hwu P
; Watowich SS
Sci Signal
2016[Sep]; 9
(447
): ra94
PMID27678219
show ga
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-? (TNF-?). 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-?-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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