β-catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8⁺ T cells. J Leukoc Biol 2014 Jan;95(1):179-90
Date
09/12/2013Pubmed ID
24023259DOI
10.1189/jlb.0613330Scopus ID
2-s2.0-84897019410 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
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 CD8⁺ 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-catenin(active) mice. DCs from DC-β-catenin(active) 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-catenin(active) 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.
Author List
Liang X, Fu C, Cui W, Ober-Blöbaum JL, Zahner SP, Shrikant PA, Clausen BE, Flavell RA, Mellman I, Jiang AMESH terms used to index this publication - Major topics in bold
AnimalsCD8-Positive T-Lymphocytes
Cross-Priming
Dendritic Cells
Immune Tolerance
Immunologic Memory
Melanoma, Experimental
Mice
Mice, Knockout
Neoplasms
beta Catenin
