β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells

Xinjun Liang, Chunmei Fu, Weiguo Cui, Julia L. Ober-Blöbaum, Sonja P. Zahner, Protul A. Shrikant, Björn E. Clausen, Richard A. Flavell, Ira Mellman, Aimin Jiang

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Whereas CD8+ T cells are essential for anti-tumor immunity, tumors often evade CD8+ T cell surveillance by immunosuppression. As the initiators of antigen-specific immune responses, DCs are likely to play a central role in regulating the balance between immunity and tolerance to tumor antigens and are specialized in their ability to cross-present exogenous tumor antigens on MHC class I molecules to initiate CD8+ T cell immunity. However, it remains unclear whether and how tumors modulate DC functions to suppress CD8+ T cell responses. We have shown previously that β-catenin signaling in DCs promotes DC-mediated CD4+ T cell tolerance. Here, we tested the hypothesis that β-catenin in DCs mediates tumor-induced suppression of CD8+ T cell immunity by inhibiting the ability of DCs in cross-priming. β-Catenin was activated in DCs by multiple tumors in vivo and in vitro. B16 melanoma-bearing mice, when vaccinated with DC-targeting anti-DEC-205 mAb fused with tumor antigens, exhibited dampened CD8+ immunity, similar to DC-β-cateninactive mice. DCs from DC-β-cateninactive and tumor-bearing mice were deficient in cross-priming, and antigen-specific CD8+ T cells primed in these mice resulted in dampened CD8+ memory responses. Importantly, DC-β-catenin-/- mice completely abrogate tumor-mediated inhibition of cross-priming, suggesting that tumor-induced inhibition of cross-priming is dependent on β-catenin. Finally, enhancing cross-priming at the priming or recall phase rescued β-catenin-suppressed CD8+ immunity in DC-β-cateninactive and tumor-bearing mice. Thus, β-catenin-mediated inhibition of cross-priming represents a new and potentially general mechanism that tumors employ to achieve immunosuppression.

Original languageEnglish (US)
Pages (from-to)179-190
Number of pages12
JournalJournal of Leukocyte Biology
Volume95
Issue number1
DOIs
StatePublished - Jan 2014

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Keywords

  • Anti-tumor immunity
  • DC vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Cite this

Liang, X., Fu, C., Cui, W., Ober-Blöbaum, J. L., Zahner, S. P., Shrikant, P. A., Clausen, B. E., Flavell, R. A., Mellman, I., & Jiang, A. (2014). β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells. Journal of Leukocyte Biology, 95(1), 179-190. https://doi.org/10.1189/jlb.0613330