Evidence for a BCR-ABL-induced anergic state of iNTK cells in chronic myeloid leukemia patients at diagnosis (162.32)

Abstract

Abstract Chronic myeloid leukemia (CML) is a myeloproliferative disorder, caused by the presence of the Philadelphia chromosome and the consecutive chimerical BCR-ABL oncoprotein, with deregulated tyrosine kinase (TK) activity. Whether invariant NKT (iNKT) cells, which are documented for their anti-tumoral activity, are affected during the disease remains unknown. Here, we addressed this issue by showing that proliferation rate of blood iNKT cells in response to their cognate ligand α-galactosylceramide is altered in CML patients at diagnosis, as compared to healthy subjects. This anergic state of iNKT cells was associated with both intrinsic and APC-dependent alterations. Furthermore, expression of perforin and CD95-L as well as that of PLZF, a transcription factor that is requisite for maintenance of functions of iNKT cells, were also decreased in patients at diagnosis. Importantly, all these functional impairments were corrected in patients who achieved a complete cytogenetic remission with the TK inhibitor imatinib mesylate (IM) or IFN-γ therapy. Together, these data demonstrate that chronic phase CML is associated with an acquired but potentially reversible defect in iNKT cells. Given the critical role of iNKT cells in tumor surveillance, it is tempting to propose that iNKT cell dysfunctions associated with CML thus could be one way used by tumors to escape from the anti-CML immune response while IM and IFN-γ exert their anti-leukemic effects in part in targeting iNKT cells.