Melanoma-specific murine CD8+ T cells engineered to mimic TLR stimulation by expressing a CD8α:MyD88 fusion protein had a lower threshold of T cell activation and improved the control of weakly immunogenic melanoma in vivo in a TCR-dependent fashion by enhancing production of IFNγ, TNFα, and co-stimulatory molecules, reducing exhaustion markers, and shifting the tumor microenvironment to a state more favorable to anti-tumor response.
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 CD8alpha and MyD88 (CD8alpha:MyD88) to enhance CD8+ T cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8alpha: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. CD8alpha: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, CD8alpha:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T cell responses to tumor antigens.
Author Info: (1) Marlene and Stewart Greenebaum Comprehensive Cancer Center, Univ of MD Baltimore. (2) Marlene and Stewart Greenebaum Cancer Center, University of Maryland. (3) Marlene and Stew
Author Info: (1) Marlene and Stewart Greenebaum Comprehensive Cancer Center, Univ of MD Baltimore. (2) Marlene and Stewart Greenebaum Cancer Center, University of Maryland. (3) Marlene and Stewart Greenebaum Comprehensive Cancer Center, Univ of MD Baltimore. (4) Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland. (5) Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore. (6) Microbiology and Immunology, University of Maryland/Greenebaum Cancer Center. (7) Epidemiology and Public Health, University of Maryland. (8) Department of Pediatrics, University of Arkansas for Medical Sciences. (9) Department of Microbiology and Immunology, University of Maryland edavila@som.umaryland.edu.
