CD155/PVR determines Acute Myeloid Leukemia targeting by Delta One T cells.

Relapsed or refractory Acute Myeloid Leukemia (AML) remains a major therapeutic challenge. We have recently developed a V1+  T-cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here we dissected the role of NK-cell receptor ligands in AML cell recognition by DOT-cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/PVR and CD112/Nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key non-redundant and synergistic contributions of PVR and B7-H6, but not Nectin-2, to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT-cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT-cells. These data provide new mechanistic insight into tumor-targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT-cell-based clinical trials.