A Synthetic CD8α:MyD88 Coreceptor Enhances CD8 + T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-12, Vol.77 (24), p.7049-7058
• Main Authors: Kaczanowska, Sabina, Joseph, Ann Mary, Guo, Jitao, Tsai, Alexander K, Lasola, Jackline Joy, Younger, Kenisha, Zhang, Yuji, Gonzales, Cruz Velasco, Davila, Eduardo
• Format: Article
• Language: English
• Subjects: Animals; Antigen (tumor-associated); Antigen presentation; Antigen Presentation - drug effects; Antigen Presentation - immunology; Antigens; Antigens, Neoplasm - immunology; Antitumor activity; Cancer; CD8 antigen; CD8 Antigens - genetics; CD8 Antigens - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - physiology; Cell activation; Cell proliferation; Cells, Cultured; Costimulator; Cytotoxicity, Immunologic - drug effects; Cytotoxicity, Immunologic - genetics; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Exhaustion; Fusion protein; Gene Expression Regulation, Neoplastic - immunology; Histocompatibility antigen HLA; Humans; Immune Tolerance - drug effects; Immune Tolerance - genetics; Immunogenicity; Immunosuppression; Immunotherapy; Lymphocytes; Lymphocytes T; Macrophages; Metastases; Mice; Mice, Inbred C57BL; Mice, Transgenic; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Proteins; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacology; T cell receptors; Toll-like receptors; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0653

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 CD8α and MyD88 (CD8α:MyD88) to enhance CD8 T-cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α: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. CD8α: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, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T-cell responses to tumor antigens. .