β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells
Journal of Leukocyte Biology , Volume 95 - Issue 1 p. 179- 190
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.
|Journal of Leukocyte Biology|
|Organisation||Department of Immunology|
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. doi:10.1189/jlb.0613330