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

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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 - 2014
Externally publishedYes

Fingerprint

Cross-Priming
Catenins
Immunosuppression
T-Lymphocytes
Immunity
Neoplasms
Neoplasm Antigens
Aptitude
CD8 Antigens
Experimental Melanomas
Histocompatibility Antigens Class II

Keywords

  • Anti-tumor immunity
  • DC vaccine

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

Cite this

Liang, X., Fu, C., Cui, W., Ober-Blöbaum, J. L., Zahner, S. P., Shrikant, P. A., ... 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

β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells. / Liang, Xinjun; Fu, Chunmei; Cui, Weiguo; Ober-Blöbaum, Julia L.; Zahner, Sonja P.; Shrikant, Protul A.; Clausen, Björn E.; Flavell, Richard A.; Mellman, Ira; Jiang, Aimin.

In: Journal of Leukocyte Biology, Vol. 95, No. 1, 2014, p. 179-190.

Research output: Contribution to journalArticle

Liang, X, Fu, C, Cui, W, Ober-Blöbaum, JL, Zahner, SP, Shrikant, PA, Clausen, BE, Flavell, RA, Mellman, I & Jiang, A 2014, 'β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells', Journal of Leukocyte Biology, vol. 95, no. 1, pp. 179-190. https://doi.org/10.1189/jlb.0613330
Liang, Xinjun ; Fu, Chunmei ; Cui, Weiguo ; Ober-Blöbaum, Julia L. ; Zahner, Sonja P. ; Shrikant, Protul A. ; Clausen, Björn E. ; Flavell, Richard A. ; Mellman, Ira ; Jiang, Aimin. / β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells. In: Journal of Leukocyte Biology. 2014 ; Vol. 95, No. 1. pp. 179-190.
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