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

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.

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+T cells through regulation of IL-10

“…Consistently, activation of β-catenin in DCs has recently been shown to suppress CD8 + T-cell immunity in a DC-targeted vaccine model (5), suggesting that β-catenin in DCs might similarly serve as a tolerizing signal that shifts the balance between CD8 + T-cell immunity and tolerance. Although the underlying mechanisms of how β-catenin mediates CD8 + T-cell tolerance remain largely unclear, we have shown that activation of β-catenin in DCs genetically or induced by tumors suppresses CD8…”

“…Currently, studies on β-catenin have supported its role in promoting tolerance function of DCs (2)(3)(4)(5)(40)(41)(42)(43). Given that deletion of β-catenin in DCs abrogated tumor-induced inhibition of cross-priming (5), we were surprised that DC-β-catenin −/− mice generated reduced antitumor immunity upon vaccination.…”

“…DC-β-catenin active (CD11c-Cre Cross-Priming Assays and DC-T-Cell Cocultures. In vivo cross-priming assays were described previously (5). Purified CD11c + DCs were pulsed with anti-DEC-205-OVA plus CpG, and were cultured with naïve Thy1.1 + OTI cells or total CD8 + T cells.…”

“…Purified CD11c + DCs were pulsed with anti-DEC-205-OVA plus CpG, and were cultured with naïve Thy1.1 + OTI cells or total CD8 + T cells. Thy1.1 + OTI cells were stimulated and assayed for cross-priming as described (5). In some experiments, anti-IL-10 (10 μg/mL) was added to the cocultures and during in vitro restimulation; rapamycin (10 ng/mL) was added to DCs 20 min before CpG treatment.…”

“…As β-catenin regulates DC maturation and differentiation (3, 13), we asked whether they could contribute to impaired cross-priming observed in DC-β-catenin active mice that express constitutively active β-catenin in their DCs (5). Surprisingly, although the percentages of total CD11c + cells, CD8 + , and CD4 + conventional DCs (CD11c + B220 − ) were similar in skin-draining lymph nodes, DC-β-catenin active mice exhibited significantly higher percentage of splenic CD8…”