Pgp (MDR1)-dependent resisrance of malignant cells towards natural killer (NK) cells is reversed by IL-2 and by the Pgp inhibitor KT-5720: implications on graft versus tumor (GVT) effects in adoptive immunotherapy (B144)

Abstract

Abstract P-glycoprotein (Pgp) encoded by the MDR1 gene, may render tumor resistant to NK and CTLs mediated immunotherapy (DLI). We assessed Pgp expression on tumors and their response to DLI & tried to reverse tumor resistance towards NK cells. The KB-V1, Pgp over-expressing cell line was found significantly less sensitive to resting & IL-2 activated NK cells than its parental KB-3-1, Pgp non expressing cell line. NK-resistant Colo205 cell line expressed high level of Pgp RNA, while low expression level was found in NK-sensitive K562 cell line. The allele polymorphism C3435T of MDR1 is associated with phenotypic variations in Pgp expression, with high-, intermediate- or low-expression level of the CC, CT and TT genotypes, respectively. Both KB-V1 & Colo205 (MDR1 over-expressing and NK-resistant) cell lines carried the CC genotype while the K562 cell line (MDR1 low-expressing, and NK-sensitive) carried the TT genotype. Incubation of resting NK cells with IL-2 increases significantly the killing of both KB-3-1 & KB-V1 cell lines. The Pgp inhibitor KT-5720 increases the killing of KB-V1 cells (but not of KB-3-1 cells) by resting NK cells. In summary: Low cytolytic response of tumor cells to NK-cells is associated with high Pgp expression and the CC genotype of the MDR1 geneIL-2 & the Pgp inhibitor, KT-5720, reverse Pgp-dependent resistance of tumors towards NK cellsExposure of NK-cells to IL-2 increases their cytolytic activity. The effect of IL-2 is larger on Pgp-high expressing- than on Pgp-non expressing-target cellsSince KT-5720 is a novel Pgp inhibitor this study may lead to future clinical application of KT-5720, to increase GVT effects in adoptive immunotherapy.