The CD112-TIGIT/PVRIG Axis Mediates NK Cell Evasion in Decitabine-Treated Acute Myeloid Leukemia Cells
TL;DR
Findings identify CD112 upregulation, which is associated with enhancer demethylation, as a mechanism of drug-induced immune evasion in AML and provide a rationale for combining hypomethylating agents with blockade of the CD112-TIGIT/PVRIG axis to enhance NK cell-mediated antileukemic activity.
Abstract
Both drug resistance and immune evasion are considered to contribute to the persistence of residual AML cells and disease relapse. Natural killer (NK) cells play an important role in antileukemic immune surveillance and represent a key component of antitumor immunity in AML. Here, we investigated whether antileukemic drugs alter the susceptibility of surviving AML cells to natural killer (NK) cell-mediated cytotoxicity. AML cells surviving decitabine treatment became resistant to NK-92-mediated killing and showed marked upregulation of CD112. CD112 overexpression reduced NK-92-mediated cytotoxicity, whereas deletion of CD112 in AML cells or deletion of either TIGIT or PVRIG, two inhibitory receptors for CD112, in NK-92 cells restored cytotoxicity. Mechanistically, decitabine induced demethylation of two enhancer regions within the CD112 locus. Deletion of either enhancer attenuated CD112 upregulation, suggesting that enhancer demethylation contributes to decitabine-induced CD112 expression. Furthermore, antibody-mediated blockade of CD112 or combined blockade of TIGIT and PVRIG enhanced cytotoxicity against decitabine-treated AML cells. CD112 upregulation was also observed following azacitidine or cytarabine treatment, although the magnitude of induction varied across drugs and cell lines. These findings identify CD112 upregulation, which is associated with enhancer demethylation, as a mechanism of drug-induced immune evasion in AML and provide a rationale for combining hypomethylating agents with blockade of the CD112-TIGIT/PVRIG axis to enhance NK cell-mediated antileukemic activity.