Immunomodulatory Effects of IFNα on T and NK Cells in Chronic Myeloid Leukemia Patients in Deep Molecular Response Preparing for Treatment Discontinuation

A deep and stable molecular response (DMR) is a prerequisite for a successful treatment-free remission (TFR) in chronic myeloid leukemia (CML). In order to better identify and analyze potential candidates of successful TFR, we examined the phenotypic and functional host immune compartment in DMR patients who had received TKI treatment only (TKI-only) or had been previously treated with interferon-alpha (IFN alpha + TKI) or had received IFN alpha treatment only (IFN alpha-only). The T/NK-cell subset distribution, NK- and T-cell cytokine production, activation and maturation markers were measured in 44 patients in DMR treated with IFN alpha only (9), with IFN alpha + TKI (11) and with TKI-only (24). IFN alpha + TKI and TKI-only groups were eligible to TKI discontinuation according to the NCCN and ESMO guidelines (stable MR4 for more than two years). In IFN alpha-treated patients, we documented an increased number of lymphocytes capable of producing IFN gamma and TNF alpha compared to the TKI-only group. In INF alpha + TKI patients, the percentage of NKG2C expression and its mean fluorescence intensity were significantly higher compared to the TKI-only group and to the INF alpha-only group in the CD56dim/CD16+ NK cell subsets (INF alpha + TKI vs. TKI-only p = 0.041, p = 0.037; INF alpha + TKI vs. INF alpha-only p = 0.03, p = 0.033, respectively). Furthermore, in INF alpha-only treated patients, we observed an increase of NKp46 MFI in the CD56bright/CD16- NK cell subset that becomes significant compared to the INF alpha + TKI group (p = 0.008). Our data indicate that a previous exposure to IFN alpha substantially and persistently modified the immune system of CML patients in memory T lymphocytes, differentiated NKG2C+ ``long-lived{''} NK cells responses, even years after the last IFN alpha contact.