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

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.

Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging

“…This LGL expansion is associated with an improved anti-leukemic response in both CML and Ph+ ALL patients [ 29 , 32 , 33 , 34 , 35 ]. The CD8 + T cell response in dasatinib-mediated LGL response includes TCR-Vβ + expansion of either oligoclonal or polyclonal origin with cells resembling healthy memory CD8 + T cells [ 36 ]. Importantly, dasatinib may have an immunomodulatory role in non-conventional or innate T cells by increasing cell number, activation status and Th-1 polarization of innate αβ iNKT-cells in treated CML patients [ 37 ].…”

Immunomodulatory Activity of Tyrosine Kinase Inhibitors to Elicit Cytotoxicity Against Cancer and Viral Infection

“…In dasatinib-treated CML patients, a dominant LGLs CD8 + TCR-Vβ + expansion of either oligoclonal or polyclonal origin was recently found, reflecting multiple antigen specificities (Lissina et al, 2018). These CD8 + T-cell populations resembled healthy memory CD8 + T-cells (Lissina et al, 2018). Moreover, memory T cells are more resistant to dasatinib effects than naïve T-cells (Weichsel et al, 2008).…”