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.

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

“…16 These monocytic Low AML were shown to have poorly active mevalonate pathway. 16 This could account for a poor pAg accumulation in these blasts upon N-BP treatment that would fail to activate Vg9Vd2 T cells.…”

“…16 These monocytic Low AML were shown to have poorly active mevalonate pathway. 16 This could account for a poor pAg accumulation in these blasts upon N-BP treatment that would fail to activate Vg9Vd2 T cells. 29 We show that anti-BTN3A 20.1 mAb can sensitize N-BP-poorly sensitized primary AML blasts to Vg9Vd2T cells lysis, notably monocytic Low AML.…”

“…16 We thus assessed the level of monocytic differentiation in our samples by determining the percentage of monocytic component defined based on the SSC parameter and the level of expression of CD45 ( Fig. 5A and B).…”

“…15 However, 50% of N-BP-treated blasts still failed to enhance allogeneic gd T cells cytotoxicity in vitro, suggesting that novel-triggering agents are still warranted. 16 Among the B7-related family, the butyrophilin3A (BTN3A) subfamily comprises three isoforms (BTN3A1, BTN3A2 and BTN3A3) 17 that contain two extracellular immunoglobulin (Ig) domains (IgV and IgC) and a transmembrane domain. Only BTN3A1 and BTN3A3 contain a B30.2 cytoplasmic domain.…”

Anthocyanins from black rice (Oryza sativa) promote immune responses in leukemia through enhancing phagocytosis of macrophages in vivo

“…It has been reported that post-remission therapy is essential for AML patients with complete hematologically-defined remission. (5). It has also been reported that increased consumption of fruits and vegetables can decrease the risk of cancer (6), cardiovascular disease and atherosclerosis in humans (7).…”