A Synthetic Cd8 Alpha:Myd88 Coreceptor Enhances Cd8(+) T-Cell Responses To Weakly Immunogenic And Lowly Expressed Tumor Antigens

T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T-cell efficacy, including suboptimal T-cell receptor (TCR) activation and an immunosuppressive tumor environment. Here, we developed a fusion protein by linking CD8 alpha and MyD88 (CD8 alpha:MyD88) to enhance CD8(+) T-cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8 alpha:MyD88-engineered T cells exhibited increased proliferation and expression of effector and costimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor signaling-related proteins. CD8 alpha:MyD88-expressing T cells improved antitumor responses in mice. Enhanced antitumor activity was associated with a unique tumor cytokine/chemokine signature, improved T-cell infiltration, reduced markers of T-cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8 alpha:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T-cell responses to tumor antigens. (C) 2017 AACR.