A Comprehensive Analysis of Primary Acute Myeloid Leukemia Identifies Biomarkers Predicting Susceptibility to Human Allogeneic Vγ9Vδ2 T Cells

Allogeneic innate lymphocytes such as V gamma 9V delta 2 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 V gamma 9V delta 2 T cells. We show that 36% of primary AML samples were intrinsically susceptible to allogeneic V gamma 9V delta 2 T cells. Among several evaluated features, only UL-16 binding protein 1 (ULBP1) expression (P < 0.01) determines intrinsic AML susceptibility to allogeneic V gamma 9V delta 2 T cells. Within the intrinsically resistant AML samples, pretreatment of AML blasts with nitrogen-containing bisphosphonates (NBP) significantly induced V gamma 9V delta 2 T-cell cytotoxicity in 50% of AML samples, whereas 50% of AML samples were consistently refractory to gamma delta 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 V gamma 9V delta 2 T-cell-mediated immunotherapy.