MyD88 Co-stimulation in CD8+ T Cells Improves Tumor Immunotherapy in Allogeneic and Syngeneic Models
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AbstractImproving the efficacy of T cell therapies for solid tumors and leukemias could improve clinical outcomes. In leukemia, allogeneic hematopoietic cell transplantation and donor lymphocyte infusions can be potentially curative, however, tumor evasion of the graft-versus-leukemia effects still limit their efficacy. In the solid tumor microenvironment, immune suppressive myeloid cells inhibit T cell activation which can be detrimental to anti-tumor T cell responses. Toll-like Receptor/MyD88 signaling in cytotoxic T cells can provide a strong co-stimulation signal to improve T cell activation, function, and efficacy to counteract evasion mechanisms in hematopoietic and solid tumors. Unfortunately, TLR agonists lack specificity to T cells and may induce hyper inflammation or induce pro-tumor effects. Rather than provide TLR agonist therapy in leukemia and solid tumors, there exists potential to modify or engineer T cells to provide a direct MyD88 co-stimulus. Our research group developed a CD8α:MyD88 T cell co-receptor that mimics TLR co-stimulation in conjunction with T cell receptor activation. Our goal was to first determine whether this engineered T cell co-receptor could enhance graft-versus-leukemia responses in allogeneic hematopoietic cell transplantation and donor lymphocyte infusion therapies. In a suppressive solid tumor, we asked if MyD88 co-receptor could improve T cell activation and function in a suppressive tumor microenvironment. Using multiple experimental transplant models, we found that MyD88 co-stimulation in donor CD8+ T cells could improve the graft versus tumor response with some non-lethal increases in graft-versus-host disease. Looking further, we found that the CD8α:MyD88 co-receptor increased donor cytotoxic T cell proliferation, survival, and function in vivo. Donor CD8α:MyD88 T cells were able to directly kill tumor better than transduced controls. In the second part of this project we found that cytotoxic T cells receiving a synthetic MyD88 co-stimulation maintained strong basal activation in the presence of myeloid suppression. In the suppressive B16-GMCSF melanoma model, CD8α:MyD88 T cell were able to control tumor growth and reduce populations of suppressive myeloid cells in the tumor. These data show that augmented MyD88 co-stimulation in cytotoxic T cells could benefit patients undergoing both autologous and allogeneic T cell therapies.
University of Maryland, Baltimore
KeywordCD8+ T cells
Myeloid Differentiation Factor 88