Abstract
Adult T-cell leukemia/lymphoma (ATLL) patients have an extremely poor prognosis, partly due to their immunosuppressive state. The majority of ATLL patients have leukemic cells with phenotype similar to Tregs, prompting suggestions that ATLL cells themselves have immunosuppressive functions. In this study, we detected CD39 expression on ATLL cells, particularly frequent on aggressive subtypes. CD39 and CD73 convert extracellular adenosine triphosphate (ATP) into adenosine, a key player in Tregs’ immunosuppression. In vitro culture, both CD39+ ATLL cells and normal Tregs converted rapidly extracellular ATP to AMP, which was disturbed by CD39 inhibitors, and was negated in the CD39 knockout MJ cell line. The proliferation of cocultured CD4+/CD8+ normal T cells was suppressed by CD39+ MJ cells, but not by CD39 knockout MJ cells. Supplemented ATP was exhausted by an EG7-OVA T-cell line with stable CD39 induction, but not by mock. When these cell lines were subcutaneously transplanted into murine flanks, Poly(I:C) peritoneal administration reduced tumor size to 1/3 in mock-transplanted tumors, but not in CD39 induced tumors. Overall, we found that ATLL cells express CD39 at a high rate, and our results suggest that this helps ATLL cells escape antitumor immunity through the extracellular ATPDase-Adenosine cascade. These findings will guide future clinical strategies for ATLL treatment.
Highlights
Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm that has been linked to the human T-cell lymphotropic virus HTLV-1 [1, 2]
Color-coded heatmaps visualizing the differences in categorized gene expressions revealed that inflammation- and immunity-related genes were attenuated in ATLL cells
Our results further suggested that this enabled ATLL cells to escape the antitumor immunity of environmental cells via inhibition of the host immune response through the extracellular ATPDase-Adenosine cascade, including CD39 and their own or surrounding CD73
Summary
Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm that has been linked to the human T-cell lymphotropic virus HTLV-1 [1, 2]. Our present study started with analysis of the roles of molecules expressed in ATLL cells, which are associated with the immunosuppressive functions of Tregs. One of the suppressive mechanisms attributed to Tregs is metabolic disruption, which is partly ascribed to CD39 and CD73 expressions and the concomitant adenosine production [20,21,22] Downstream of this enzymatic cascade, CD26 ( termed dipeptidyl peptidase VI or DPP4) interacts with adenosine deaminase (ADA) and inhibits the Tregs’ immunosuppressive function by catalyzing adenosine into inosine. PBMCs from ATLL patients were separated into CD4+CD7−CADM1+ ATLL cells and adjacent CD4+CD7+ CADM1− normal T cells using a fluorescence-activated cell sorter (FACS Aria; Becton, Dickinson and Company: BD, USA) These subsets were subjected to total RNA sequencing experiments, and examinations of the expression patterns of CD39, CD73, and CD26 using flow cytometry (FACS Canto, BD). Osaka University Hospital, Ryukyu University Hospital, and Kyushu Cancer Center, and met all requirements of the Declaration of Helsinki
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