Divergent roles for antigenic drive in the aetiology of primary versus dasatinib-associated CD8+ TCR-V\u03b2+ expansions

Anna Lissina,Kristin Ladell,A John Barrett,Catherine S Lewis,Emma Gostick,Sian Llewellyn-Lacey,Andrew Herman,Mathew Clement,J Joseph Melenhorst,Kelly L Miners,Mette Ilander,Satu Mustjoki,Emma I Andersson,David A Price,Linda Wooldridge,James E Mclaren

doi:10.1038/s41598-017-18062-x

Abstract

CD8+ T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8+ T-cell receptor (TCR)-Vβ+ populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-Vβ+) and residual (TCR-Vβ−) CD8+ T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8+ TCR-Vβ+ expansions in T-LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8+ TCR-Vβ+ expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8+ TCR-Vβ+ expansions.

Highlights

CD8+ T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects
CD8+ T-cell expansions have been reported in patients undergoing treatment with the promiscuous tyrosine kinase inhibitor dasatinib, which is licensed as a first line therapeutic option in the management of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL)[11,12,13,14,15,16]
The dominant T-cell receptor (TCR)-Vβ+ expansions in T-LGLL patients were almost exclusively populated with terminally differentiated (CCR7− CD45-rheumatoid arthritis (RA)+) effector CD8+ T-cells, whereas the dominant TCR-Vβ+ expansions in dasatinib-treated CML patients were more broadly constituted across the phenotypic spectrum of CD8+ T-cells (Fig. 2A)

Summary

Introduction

CD8+ T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. CD8+ T-cell expansions have been reported in patients undergoing treatment with the promiscuous tyrosine kinase inhibitor dasatinib, which is licensed as a first line therapeutic option in the management of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL)[11,12,13,14,15,16]. In some cases, these expanded CD8+ T-cells can even mimic T-cell large granular lymphocytes (T-LGLs). The majority of these mutations affect STAT325–27, with others localizing most commonly to STAT5B28

Methods

Results

Conclusion