K+ Channel Activation Promotes Tumor infiltrating Lymphocyte (TIL) Expansion and Enhances Expression of CCR7
Autor: | Krit Ritthipichai, Marcus Machin, Michelle Simpson-Abelson, Christopher Mosychuk, Anand Veerapathran, Michael Lotze |
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Rok vydání: | 2017 |
Předmět: | |
Zdroj: | The Journal of Immunology. 198:198.1-198.1 |
ISSN: | 1550-6606 0022-1767 |
DOI: | 10.4049/jimmunol.198.supp.198.1 |
Popis: | Only two K+ channels are known to be expressed by T-cells. Activated effector T cells express high levels of Kv1.3; activated naïve and central memory T-cell subsets express high levels of KCa3.1. Overexpression of Kv1.3 in murine T-cells increases K+ efflux, improves effector function (IFNγ production) and promotes anti-tumor activity1. Inhibition of KCa3.1 suppresses murine T-cell proliferation and cytokine production. In human PBMCs and TIL, KCa3.1 expression was relatively low with upregulation observed within 24 h following stimulation with anti-CD3 and anti-CD28. The addition of the KCa3.1 agonist SKA-31 did not alter KCa3.1 expression but enhanced CCR7 expression significantly on TIL and human PBMCs. TILs propagated in the Rapid Expansion Protocol (REP) had a 1.42-fold greater expansion (p=0.002) in the presence of SKA-31 and significant increases in the CD8+CD28+ (p=0.04), CD8+CD27+(p=0.04), and CD8+CD27+CD28+subsets (p=0.002), consistent with a less differentiated phenotype. We thus demonstrate that SKA-31 treatment enhances CCR7 expression associated with memory cells, promotes TIL expansion, and attenuates T-cell differentiation. Targeting the KCa3.1 channel is a novel strategy to expand and sustain less differentiated TILs and may improve the clinical application of adoptive T-cell therapy. 1: Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature. 2016;537):539–543. |
Databáze: | OpenAIRE |
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