Natural killer cells modulation in hematological malignancies

Abstract

Hematological malignancies (HM) treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed, due to remaining minimal residual disease. Therefore, sustainment of long-term remission is crucial, using either drug maintenance treatment or by boosting or prolonging an immune response. Immune system has a key role in tumor surveillance. Nonetheless, tumor-cells evade the specific T-lymphocyte mediated immune surveillance using many mechanisms but especially by the down-regulation of the expression of HLA class I antigens. In theory, these tumor-cells lacking normal expression of HLA class I molecules should be destroyed by natural killer (NK) cells, according to the missing-self hypothesis. NK cells, at the frontier of innate and adaptive immune system, have a central role in tumor-cells surveillance as demonstrated in the setting of allogenic stem cell transplantation. Nevertheless, tumors develop various mechanisms to escape from NK innate immune pressure. Abnormal NK cytolytic functions have been described in many HM. We present here various mechanisms involved in the escape of HM from NK-cell surveillance, i.e., NK-cells quantitative and qualitative abnormalities.

Keywords: hematological malignancies; immune escape; immunotherapy; natural cytotoxicity receptors; natural killer cells.

Figure 1

The effect of KIR/HLA class I mismatch in patients undergoing allogenic stem cells transplantation (HSTC).The main challenge in HSTC is to keep the balance between conserving the graft versus leukemia (GvL) effect on the one hand and preventing risk of relapse on the other. (A) Killer cell immunoglobulin-like receptor (KIR) of donors NK cells is engaged by corresponding HLA ligand, which inhibits NK-cell function. Donor NK cells are non-alloreactive and do not kill recipient’s blasts, which leads to the relapse of patient. (B) The concept and recognition of KIR-ligand incompatibility (also known as KIR-ligand mismatch) has important implications. KIR-mismatch is an independent predictor of survival in patients. Graft versus tumor NK-cell alloreactivity reduces the risk of leukemia relapse, and markedly improves event-free survival.