The novel coreceptor CD8α:MyD88 enhances T-cell proliferation, activation, and antitumor response at low-dose IL-2 in B16 melanoma

Abstract

Abstract The gamma common chain (γc) cytokine receptor plays a central role in Type I cytokine signaling, and in the generation and expansion of antitumor T-cells. Adoptive T-cell therapies (ACT) benefit from IL-2 treatment but is limited by a short half-life and high toxicities. Reducing IL-2 mediated toxicities while retaining antitumor T-cell efficacy is needed to improve clinical outcomes in ACT-treated patients. Other γc cytokines such as IL-7 and 15 have shown benefits for ACT by increasing generation and expansion of long-lived antitumor T-cells with reduced cytokine toxicity. Our lab previously demonstrated that MyD88 (critical adaptor protein in toll-like receptor signaling) is necessary for CD8 T-cell expansion. Induced MyD88 signaling in T-cells via expression of novel coreceptor CD8a:MyD88 (CM T-cells) resulted in enhanced proliferation, activation, and durably reduced tumor size in mouse melanoma models upon ACT treatment. CM T-cells expressed higher γc receptor levels which is required for IL-2, IL-7 and IL-15. Therefore, we hypothesized that CM T-cells have increased sensitivity to γc cytokine signaling resulting in enhanced proliferation, activation, and antitumor activity. CM T cells cultured at 10–25 times lower concentrations of IL-2, -15, -7 demonstrated enhanced cell proliferation and activation and was associated with increased JAK-STAT signaling intensity and persistence. CM T-cell ACT treatment of mice with B16-F10 tumors reduced tumor growth even at the lowest IL-2 concentration (5000 IU IL-2). In conclusion, CM T-cells require lower concentrations of type I cytokines for enhanced antitumor immunity and highlights the potential of CM T-cells to improve clinical outcomes with reduced toxicities. Supported by grants from NSF GRFP, NCI (R01CA207913, P30CA046934), Dept of VA Merit Award (BX004935-01), University of Colorado Comprehensive Cancer Center (UCCCC), Leukemia and Lymphoma Society Translational Research Program