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Open AccessArticle

STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer

1
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2
MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 128; https://doi.org/10.3390/cancers12010128
Received: 26 November 2019 / Revised: 30 December 2019 / Accepted: 2 January 2020 / Published: 4 January 2020
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103+ cDC1s in mice) are necessary to mount CD8+ T cell-mediated anti-tumor immunity, whether and how tumors modulate CD103+ cDC1 function remain understudied. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10; thus, we hypothesized that STAT3 restrained anti-tumor immune responses elicited by CD103+ cDC1s. Herein, we show that in vitro-derived STAT3-deficient (Stat3∆/∆) CD103+ cDC1s are refractory to the inhibitory effects of IL-10 on Toll-like receptor 3 (TLR3) agonist-induced maturation responses. In a tumor vaccination approach, we found Stat3∆/∆ CD103+ cDC1s restrained mammary gland tumor growth and increased mouse survival more effectively than STAT3-sufficient CD103+ cDC1s. In addition, vaccination with Stat3∆/∆ CD103+ cDC1s elicited increased amounts of tumor antigen-specific CD8+ T cells and IFN-γ+ CD4+ T cells in tumors and tumor-draining lymph nodes versus phosphate-buffered saline (PBS)-treated animals. Furthermore, IL-10 receptor-deficient CD103+ cDC1s controlled tumor growth to a similar degree as Stat3∆/∆ CD103+ cDC1s. Taken together, our data reveal an inhibitory role for STAT3 in CD103+ cDC1 maturation and regulation of anti-tumor immunity. Our results also suggest IL-10 is a key factor eliciting immunosuppressive STAT3 signaling in CD103+ cDC1s in breast cancer. Thus, inhibition of STAT3 in cDC1s may provide an important strategy to improve their efficacy in tumor vaccination approaches and cDC1-mediated control of anti-tumor immunity. View Full-Text
Keywords: CD103+ dendritic cells; cDC1; STAT3; breast cancer; immunotherapy; tumor vaccine; immunosuppression CD103+ dendritic cells; cDC1; STAT3; breast cancer; immunotherapy; tumor vaccine; immunosuppression
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Chrisikos, T.T.; Zhou, Y.; Li, H.S.; Babcock, R.L.; Wan, X.; Patel, B.; Newton, K.; Mancuso, J.J.; Watowich, S.S. STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer. Cancers 2020, 12, 128.

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