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

TLDR: Testing 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 found that it represents a new and potentially general mechanism that tumors employ to achieve immunosuppression.

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 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