A comprehensive analysis of primary acute myeloid leukemia identifies biomarkers predicting susceptibility to human allogeneic Vγ9Vδ2 T cells.

Abstract

Allogeneic innate lymphocytes such as Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy as they provide MHC-unrestricted antitumor activity without clinical evidence for inducing graft-versus-host disease (GvHD). However, current cellular immunotherapy approaches lack predictive biomarkers identifying patient cohorts most susceptible to immune attack. For this purpose we performed a comprehensive analysis of clinical, genetic, metabolic, and immunophenotypic features of 19 primary acute myeloid leukemia (AML) samples and correlated these factors with AML blast recognition by allogeneic Vγ9Vδ2 T cells. We show that 36% of primary AML samples were intrinsically susceptible to allogeneic Vγ9Vδ2 T cells. Among several evaluated features, only UL-16 binding protein 1 (ULBP1) expression (P<0.01) determines intrinsic AML susceptibility to allogeneic Vγ9Vδ2 T cells. Within the intrinsically resistant AML samples, pretreatment of AML blasts with nitrogen-containing bisphosphonates (NBP) significantly induced Vγ9Vδ2 T-cell cytotoxicity in 50% of AML samples, whereas 50% of AML samples were consistently refractory to γδ T-cell cytolysis. Activity of the mevalonate pathway (P<0.05) and myelomonocytic differentiation of AML (P<0.05) correlated with sensitivity of primary AML samples toward NBP pretreatment. In conclusion, this study identifies subsets of AML patients most likely to benefit from allogeneic Vγ9Vδ2 T-cell-mediated immunotherapy.