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12P - IL-18 improves the anti-cancer immunity of human gamma delta T cells against prostate cancer (ID 126)
- Mohanad H. Nada (Sulaymaniyah, Iraq)
- Mohanad H. Nada (Sulaymaniyah, Iraq)
- Auter J. Hussein (Sulimani, Iraq)
- Hong Wang (Iowa City, IA, United States of America)
- Craig T. Morita (Iowa City, United States of America)
Abstract
Background
During cancer development, IL-18 plays both positive and negative roles. IL-18 can promote tumor progression or metastasis, mainly through its effect on VCAM-1 and VEGF production. In contrast, IL-18 has been proven to enhance immunity against several kinds of tumors including melanoma and liver cancer. Due to its impact on IFN-γ production, IL-18 enhances anti-tumor activity by NK and Th1. We have previously shown that pulse stimulation with zoledronate and IL-2 or IL-15 greatly enhance the expansion, and anti-tumor activity of Vγ2Vδ2 T cells. Given the importance of IL-18 on the expansion, differentiation, and function of NK and Th1 cells, we hypothesized that expansion, memory and anti-immunity function of Vγ2Vδ2 T cells can be further optimized by using IL-18 in combination with IL-2 or IL-15 cytokines in prostate cancer settings.
Methods
We used fresh and frozen PBMCs obtained from random healthy donors. Ex vivo expansion for gamma delta T cells was done by pulsing with zoledronate in the presence of IL-2, IL-15, and/or IL-18. Multicolor Flow Cytometry LSR II was used to assess the cell functionality by measuring cytokines expression (IFN-γ, and TNF-a). Anti-cancer cytotoxicity was measured by CD107a expression after co-culturing with target cells. Human prostate cancer PC-3 cell line was used as target cells for activated Vγ2Vδ2 T cells. CD27 and CD28 were used to quantify the memory subsets of Vγ2Vδ2 T cells.
Results
Along with zoledronate pulse stimulation, adding IL-18 to IL-2 or IL-15 has significantly increased the absolute cell number of activated Vγ2Vδ2 T cells. Also, IFN-γ secretion has markedly increased when IL-18 added to the culture compare to IL-2 or 15 alone. Our findings showed different memory subset distribution based on the cytokines combination. IL-18 seems to maintain high central/early memory subsets with IL-2 and more late memory with IL-15. More importantly, IL-18 addition has increased the CD107a expression on activated Vγ2Vδ2 T cells when co-cultured with sensitized human prostate cancer cell line.
Conclusion
Our findings conclude that using IL-18 in combination with IL-2 or IL-15 results in increasing the yield, balancing out the memory subsets, and promoting the anti-cancer immunity of human Vγ2Vδ2 T cells.
Legal entity responsible for the study
Department of Internal Medicine, The University of Iowa Carver College of Medicine, USA.
Funding
Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Grant 2I01 BX000972-05) and the National Institutes of Health, National Cancer Institute, Grants CA097274 (University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence) and P30 CA086862 (Core Support) to C.T.M. C.T.M. is the Kelting Family Scholar in Rheumatology. M.H.N. was supported in part by the Higher Committee for Education Development in Iraq and National Institutes of Health Grant 5 T32 AI007485.
Disclosure
All authors have declared no conflicts of interest.