The CD112-TIGIT/PVRIG Axis Mediates NK Cell Evasion inDecitabine-Treated Acute Myeloid Leukemia Cells

A study examines how certain drugs used to treat acute myeloid leukemia (AML) can render the disease more resistant to the immune system. Researchers found that the CD112-TIGIT/PVRIG axis, which involves natural killer (NK) cells and their inhibitory receptors, plays a significant role in this immune evasion.

Decitabine, a hypomethylating agent, was shown to cause demethylation of specific enhancer regions within the CD112 gene. This demethylation led to increased expression of CD112 on AML cells, which in turn reduced the effectiveness of NK-92 cells in killing the disease cells. When the CD112 gene was deleted in NK-92 cells, or when either TIGIT or PVRIG, the two inhibitory receptors for CD112, was deleted, NK-92 cells regained their cytotoxic ability against decitabine-treated AML cells.

Moreover, the study found that antibody-mediated blockade of CD112 or a combined blockade of TIGIT and PVRIG further enhanced cytotoxicity against decitabine-treated AML cells. CD112 upregulation was also observed following treatment with other drugs such as azacitidine or cytarabine, although the extent of induction varied between different drugs and cell lines.

These findings suggest that CD112 upregulation, linked to enhancer demethylation, is a mechanism of drug-induced immune evasion in AML. The study provides a rationale for combining hypomethylating agents with blockade of the CD112-TIGIT/PVRIG axis to boost NK cell-mediated antileukemic activity.