An inhibitor of programmed death ligand 1 enhances natural killer cell-mediated immunity against malignant melanoma cells

Abstract

Since ionizing radiation has showed the dramatic effect to kill the cancer cells through direct DNA damage as well as triggering anti-cancer immune responses including induction of NKG2D ligands, it has used for long time to treat many cancer patients. However, it has been known that radiotherapy might promote the remnant cancer cells to escape immune system and metastasis. One of the suggested ways of immune evasion is induction of a ligand for programmed death-1 (PD-L1) in head and neck cancer, bladder cancer and lung cancer cells which engages the receptor, programmed death-1 (PD-1) in immune cells. PD-1/PD-L1 axis transduces the inhibitory signal and suppresses the adaptive immunity. However, their role in innate immunity remains poorly understood. Therefore, we investigated whether ionizing radiation could change the expression of PD-L1 in malignant melanoma cells and the receptor, programmed death-1 (PD-1), in NK-92 cells. Surface PD-L1 levels on melanoma cells were increased by ionizing radiation in a dose-independent manner but the level of PD-L1 was not changed significantly in NK-92 cells. Radiation-induced PD-L1 suppressed the activity of the NK-92 cells against melanoma cells despite of upregulation of NKG2D ligands. Furthermore, activated NK cells had high level of PD-1 and could not kill PD-L1+ melanoma cells effectively. When we used PD-L1 inhibitor or silenced PD-L1 gene, inhibited PD-1/PD-L1 axis reversed the activity of the suppressed NK cells. Through these results, we supposed that PD-1/PD-L1 blockade could enhance the immune responses of NK cells against melanoma cells after radiotherapy and might overcome the PD-L1 mediated radioresistance of cancer cells.

Early TRAIL-engagement elicits potent multimodal targeting of melanoma by CD34+ progenitor cell-derived NK cells

“…This secretory response may thus serve as an early indicator of the high susceptibility of MEL-BRO to NK cytotoxicity which was observed at later timepoints. SK-MEL-28 showed very low susceptibility to UCB CD34 + progenitor cell-derived NK cells, which has also been reported for NK-92, 45 but still induced significant release of granzyme A, B and granulysin in the supernatant. However, only a slight increase in E:T ratio was still sufficient to achieve more enhanced cytotoxicity.…”

Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells

“…PD-L1 upregulation prevents activation of T cells and NK cells [181]. Therefore, PD-L1-mediated immune escape is also an important cause of radioresistance [182][183][184]. Mechanisms underlying immunosuppression caused by radiation are summarized in Table 3.…”

Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression

“…However, along with this increase in NKG2D ligands, there was also an induction of PDL-1, diminishing the potential of NK cell-mediated killing [185]. A recent study by Lee et al suggested that radiotherapy could induce expression of MICA, MICB, ULBP1, ULBP2, and ULBP3 in melanoma cells, but the concurrent induction of PD-L1 on the cells diminished the potential cytotoxic effect of the NK-92 cell line [186].…”