title: 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.
authors.affiliation: 2.Roswell Park Cancer Institute, Buffalo, NY 14263, USA. aimin.jiang@roswellpark.org.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Liang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Fu
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cui
authors.forename: Julia L
authors.initials: JL
authors.lastname: Ober-Blöbaum
authors.forename: Sonja P
authors.initials: SP
authors.lastname: Zahner
authors.forename: Protul A
authors.initials: PA
authors.lastname: Shrikant
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.forename: Aimin
authors.initials: A
authors.lastname: Jiang
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D007156:Immunologic Memory; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin
keywords: DC vaccine; anti-tumor immunity