Increased Expression of TIGIT/CD57 in Peripheral Blood/Bone Marrow NK Cells in Patients with Chronic Myeloid Leukemia

Abstract

The antitumor activity of NK cells in patients with chronic myeloid leukemia (CML) is inhibited by the leukemia microenvironment. Recent studies have identified that the expression of TIGIT, CD57, and KLRG1 is related to the function, maturation, and antitumor capabilities of NK cells. However, the characteristics of the expression of these genes in the peripheral blood (PB) and bone marrow (BM) from patients with CML remain unknown. In this study, we used multicolor flow cytometry to assay the quantity and phenotypic changes of NK cells in PB and BM from de novo CML (DN-CML) and CML patients acquiring molecular response (MR-CML). We found that the expression of TIGIT, which inhibits NK cell function, is increased on CD56+ and CD56dim NK cells in DN-CML PB compared with those in healthy individuals (HIs), and it is restored to normal in patients who achieve MR. We also found that the expression of CD57 on NK cells was approximately the same level in PB and BM from DN-CML patients, while decreased CD57 expression was found on CD56+ and CD56dim NK cells in HI BM compared with PB. Additionally, those two subsets were significantly increased in DN-CML BM compared to HI BM. The expression of CD57 correlates with replicative senescence and maturity for human NK cells; therefore, the increase in TIGIT on PB NK cells together with an increase in CD57 on BM NK cells may explain the subdued NK cell antileukemia capacity and proliferative ability in DN-CML patients. These results indicate that reversing the immune suppression of PB NK cells by blocking TIGIT while improving the proliferation of BM NK cells via targeting CD57 may be more effective in removing tumor cells.

Terminal differentiation of bone marrow NK cells and increased circulation of TIGIT+ NK cells may be related to poor outcome in acute myeloid leukemia

“…This result is the same as our observation in CML patients, 34 indicating that there were more mature NK cells that accumulate in the BM of AML-DN patients, which may impact patient survival. Previously, Chretien et al divided AML patients into three subtypes based on NK cell maturation and found that patients with more immature NK cells had reduced relapse-free and overall survival, suggesting that diseaseinduced alterations in NK cell maturation affect patient outcome.…”

“…In this study, we were surprised to find that CD56 dim CD57 + NK cells accumulate in the BM of AML‐DN patients but not in PB. This result is the same as our observation in CML patients, 34 indicating that there were more mature NK cells that accumulate in the BM of AML‐DN patients, which may impact patient survival. Previously, Chretien et al.…”

“…There is plenty of evidence supporting the notion that NK cells from various cancers also suffer from exhaustion, which paves the way for immune escape and metastasis for cancer cells. 8,15,19,20,33,34 TIGIT and KLRG1 are two inhibitory immune receptors that have been found to be highly expressed in various tumors and leukemia-infiltrating NK cells, including breast cancer, 20,21 and myelodysplastic syndrome (MDS), 19 and their blockage correlate with improved NK anti-tumor capacity. the level of expression of these receptors in NK cells in AML patients remains controversial and unclear.…”

Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies

“…Similarly, NK cells display low expression of NCR, NKG2C, NKG2D in CML, which is rejuvenated post-TKI ( 101 , 107 , 108 ). Expression of inhibitory molecules (PD-1, TIGIT) appear to be elevated in de novo CML, and these levels change in individuals achieving a molecular response ( 109 , 110 ). A significant decrease in NKG2D and DNAM-1 expression was observed in MDS, and was associated with the impaired killing of MDS blasts ( 111 ).…”

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

“…To evade this, AML cells express low levels of CD155 and CD112 which results in attenuation of NK cell cytolytic towards AML blasts [ 91 , 92 ]. Similarly, TIGIT expression was observed on CD57+ NK cells in CML which might be a reason of NK cell dysfunction in CML [ 93 ]. Similar results were obtained in studies on TIGIT in AML [ 94 , 95 ].…”