Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

Abstract

The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8 þ T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27 À CD57 þ ) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8 high and CD8 low T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8 þ T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-c and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon.

Dasatinib Reversibly Disrupts Endothelial Vascular Integrity by Increasing Non-Muscle Myosin II Contractility in a ROCK-Dependent Manner

“…Many studies have reported the immune-related adverse effects of dasatinib (7,(27)(28)(29)(30)(31)(32)(33). However, these side effects do probably not account for all the observed deleterious effects of the treatment in human patients, for example, pleural effusions and bleeding diathesis.…”

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

“…Therefore, it is conceivable that once the suppressive effect on T cells wears off, secreted IL-12 may be the driving factor. Bacterial infection or viral reactivation such as cytomegalovirus, which has been reported to be associated with dasatinibinduced hyperleukocytosis, 6 would qualify as the inflammatory trigger. In concert with the described inhibition of regulatory T cells by dasatinib, as reported in vitro 41 and in vivo, 42 these mechanisms may lead to unrestricted CD8 proliferation in the clinical setting, along with a better clinical response against the underlying leukemic disease.…”

“…4 Hyperproliferative T-cell and natural killer (NK)-cell responses are seen frequently and are associated with severe adverse effects such as colitis, pleuritis, and pulmonary hypertension. [5][6][7] However, the occurrence of such hyperinflammatory effects is associated with a better prognosis regarding the underlying leukemia. 8 Somewhat paradoxically, the patients may experience severe functional impairment of their T cells 9 because of blockade of T-cell receptor (TCR) triggering via inhibition of Lck.…”

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

“…8,9 The limited in vitro data available with second-generation TKIs nilotinib (Novartis) and dasatinib (BristolMyers Squibb) show impaired antigen-specific T-cell responses [10][11][12][13][14][15] ; however, recent studies report rapid mobilization and expansion of BCR-ABL-negative lymphoid cells in dasatinib-treated patients. [16][17][18] Few studies have examined the impact of TKIs on B-cell responses to antigen in vivo, 19 although hypogammaglobulinemia has been reported in CML patients treated with imatinib. 20 A recent murine study reported that imatinib may directly impair class-switch recombination following B-cell activation through downregulation of activationinduced cytidine deaminase.…”