A synthetic CD8{alpha}:MyD88 co-receptor 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 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 co-stimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor (TLR) signaling-related proteins. CD8α:MyD88-expressing T cells improved anti-tumor responses in mice. Enhanced anti-tumor 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.

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