ABSTRACT
Mucosal-associated invariant T-cells (MAIT) are unconventional T-cells with cytotoxic and pro-inflammatory properties. Previous research has reported contradictory findings on their role in cancerogenesis with data being even scarcer in haematological malignancies. Here, we report the results of a systematic analysis of MAIT cells in treatment-naïve patients with a broad range of haematological malignancies. We analysed peripheral blood of 204 patients and 50 healthy subjects. The pool of haematological patients had a statistically significant lower both the absolute value (median values, 0.01 × 109/L vs. 0.05 × 109/L) of MAIT cells and their percentage (median values 0.94% vs. 2.56%) among T-cells compared to the control group. Separate analysis showed that the decrease in the absolute number of MAIT cells is significant in patients with acute myeloid leukaemia, myeloproliferative neoplasms, plasma cell myeloma, B-cell non-Hodgkin lymphomas, otherwise not specified, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma compared to the control population. Furthermore, in haematological malignancies, MAIT cells overexpress PD-1 (average values, 51.7% vs. 6.7%), HLA-DR (average values, 40.2% vs. 7%), CD38 (average values, 25.9% vs. 4.9%) and CD69 (average values, 40.2% vs. 9.2%). Similar results were obtained when comparing patients with individual malignancies to the control population. Our data show that the depletion of circulating MAIT cells is a common observation in a broad spectrum of haematological malignancies. In addition to their reduced numbers, MAIT cells acquire an activated/exhausted phenotype.
Subject(s)
Hematologic Neoplasms , Mucosal-Associated Invariant T Cells , Programmed Cell Death 1 Receptor , Humans , Mucosal-Associated Invariant T Cells/immunology , Hematologic Neoplasms/immunology , Male , Female , Middle Aged , Aged , Adult , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Antigens, CD/metabolism , Aged, 80 and over , Antigens, Differentiation, T-Lymphocyte/metabolism , Lymphocyte Count , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/immunology , Immunophenotyping , Young Adult , Membrane Glycoproteins/immunology , Lectins, C-TypeABSTRACT
The purpose of this study was to evaluate passive vs. proton-dependent active transport mechanisms of salicylic acid (SA) and four structurally related anions. Transport was studied across Caco-2 cell monolayers and artificial lipid membranes (PAMPA) under pH-gradient and iso-pH conditions. Kinetic permeability parameters were provided by bidirectional Caco-2 experiments and concentration-dependency measurements. The transport route and putative transporters involved in SA transport were studied using EDTA and several inhibitors. SA and lipophilic 5-chlorosalicylic acid and 2-hydroxy-1-naphthoic acid reached saturation with increasing compound concentration indicating active transport. Permeation of 5-hydroxysalicylic acid and 5-hydroxyisophthalic acid was not saturated indicating passive transport. PAMPA with pure passive diffusion underestimated the transport of SA compared to Caco-2. Opening up the paracellular tight junctions by EDTA did not increase the transport of SA under the pH-gradient conditions confirming the hypothesis of pure transcellular transport of SA. Active transport of SA remained concentration-dependent even without the pH-gradient, and was reduced by the known MCT1 and OATP-B inhibitors and structurally related anions. Overall, several permeability test protocols are needed to obtain a more complete picture of transport properties of salicylic acid and structurally related compounds.
