Natural killer cell receptors and ligand variants modulate response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm treated with tyrosine kinase inhibitors (TKIs). Although survival rates have improved, response to these treatments is highly heterogeneous. Variations in response rates may be due to different causes such as, treatment adherence, mutations in the BCR-ABL1 gene, clonal evolution and amplification of the BCR-ABL1 gene, but innate immune response is also considered to play a very important role and, specifically, NK cell activity through their receptors and ligands, could be determinant. The aim of this retrospective study was to explore the role of different activating and inhibiting KIR genes as well as the activating NKG2D receptor, present in NK cells, and also their respective ligands, HLA-A, -B, -C, -G, -F, MICA and MICB, in the progression of 190 patients with CML and treated at two hospitals from Barcelona between 2000 and 2019. Early molecular response (EMR), major molecular response (MMR) or MR3.0 and deep molecular response (DMR) or MR4.0 were correlated. As control samples, healthy donors from the Barcelona Blood Bank were analyzed. The presence of KIR2DL2/KIR2DS2 was associated with the achievement of EMR, MR3.0, and MR4.0. Carriers of the higher expression NKG2D variant and MICA*009:01 were also likely to achieve molecular response (MR). The most remarkable difference between CML patients and controls was a higher frequency of the lower expression NKG2D variant in CML patients. In summary, our results showed that activating NK receptor phenotypes might help to achieve MR and DMR in CML patients treated with TKIs although confirmatory studies are necessary.