6533b7d5fe1ef96bd1264960

RESEARCH PRODUCT

Beta-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8(+) T cells

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Tumors activate -catenin in DCs to suppress CD8 immunity by inhibiting cross-priming; -catenin-suppressed CD8 immunity could be rescued by enhancing cross-priming. 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 -catenin signaling in DCs promotes DC-mediated CD4(+) T cell tolerance. Here, we tested the hypothesis that -catenin in DCs mediates tumor-induced suppression of CD8(+) T cell immunity by inhibiting the ability of DCs in cross-priming. -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--catenin(active) mice. DCs from DC--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--catenin(-/-) mice completely abrogate tumor-mediated inhibition of cross-priming, suggesting that tumor-induced inhibition of cross-priming is dependent on -catenin. Finally, enhancing cross-priming at the priming or recall phase rescued -catenin-suppressed CD8(+) immunity in DC--catenin(active) and tumor-bearing mice. Thus, -catenin-mediated inhibition of cross-priming represents a new and potentially general mechanism that tumors employ to achieve immunosuppression.