Generating dual function highly proinflammatory cytolytic and antigen-presenting gamma-delta T cells to target cancers
Cheryl Lai-Lai Chiang, Who-Whong Wang, Han Chong Toh*, Chloe Yeo#
National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610
Human gamma-delta T cells recognize tumors in a HLA-unrestricted manner and efficiently kill a broad range of tumors. A recent meta-analysis demonstrated that tumor-infiltrating human gamma-delta T cells as one of the most predictive markers associated with good prognosis in 25 different cancers. Due to the ease of expanding Vgamma9Vdelta2 T cells from peripheral blood, it is the most commonly used subtype in clinics. We have optimized a novel and robust protocol for large-scale expansion of Vgamma9Vdelta2 T cells by investigating the use of different culture media, serum and interleukin combinations. We also defined a set of criteria (i.e. phenotype, cytokine profile, tumor cytolysis and antigen presentation to CD4+ and CD8+ T cells) to evaluate the potency of the generated Vgamma9Vdelta2 T cells. By using a combination of Optimizer T cell media supplemented with defined FBS, IL-2, IL-15 and IL-21, we expanded Vgamma9Vdelta2 T cells to more than 50-fold (P = 0.033) of approximately 90% purity (P = 0.017) after 10 days of culture. The expanded Vgamma9Vdelta2 T cells showed desirable tumor cytolytic (NKG2D), antigen-presenting (HLA-DR, CD86, CD83 and CD40) and effector (CCR7 and CD27) phenotypic markers, as well as strongly cytolytic towards Hep3B (hepatocellular), C666-1 (nasopharyngeal), DLD-1 (colorectal) and K562 tumor lines. These generated Vgamma9Vdelta2 T cells are more efficient than monocyte-derived Day 7 DCs in stimulating the proliferation of naïve CD4+ and CD8+ T cells and activating EBV and NY-ESO-1-specific CD8+ T cells in 3 individuals. Currently, we are evaluating the ability of these Vgamma9Vdelta2 T cells to control tumors in vivo in NSG mouse tumor model. This study provides important insight into the anti-tumor and antigen-presenting properties of Vgamma9Vdelta2 T cells to optimize T cell-based cancer immunotherapy.
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