Natural killer cells and malignant haemopathies: a model for the interaction of cancer with innate immunity

Abstract

Despite recent progress in the therapeutic approach of malignant haemopathies, their prognoses remain frequently poor. Immunotherapy offers an alternative of great interest in this context but defect or abnormal expression of human leukocyte antigens (HLA), frequently observed in cancer cells, limits its efficiency. Natural killer (NK) cells, which are able to kill target cells in a HLA-independent way, represent a novel tool in the treatment of haematological malignancies. Abnormal NK cytolytic function is observed in all the haematological malignancies studied, such as acute leukaemia, myelodysplastic syndromes or chronic myeloid/lymphoid leukaemia. Several mechanisms are involved in the alterations of NK cytotoxicity: decreased expression of activating receptors, increased expression of inhibitory receptors or defective expression of NK ligands on target cells. Further studies are needed to identify how each type of haematological malignancy escapes from the innate immune response. Attempts to increase the expression of activating receptors, to counteract inhibitory receptors expression, or to increase NK cell cytotoxic capacities could overcome tumour escape from innate immunity. These therapies are based on monoclonal antibodies or culture of NK cells in presence of cytokines or dendritic cells. Moreover, many novel drugs used in haematological malignancies [tyrosine kinase inhibitors, IMIDs(®), proteasome inhibitors, demethylating agents, histone deacetylase inhibitors (HDACis), histamine dihydrochloride] display interesting immunomodulatory properties that affect NK cells. These data suggest that combined modalities associating cytotoxic drugs with innate immunity modulators may represent a major breakthrough in tumour eradication.

Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

“…NK cells are early responders of the innate immune response that can exert potent activity against AML cells without the requirement of prior sensitization, making them good candidates for cancer immunotherapy [9,20,43,67].…”

Distribution of lymphocyte subpopulations in patients with polycythemia vera

“…This raises the question of abnormalities of immune cells or immune escape of PV progenitor cells. Immunologic abnormalities have been described in most heamopathies, more particularly regarding the innate immunity [1]. Moreover, several abnormalities have already been described in PV: decreased number of B and T cells [2], increased percentage of CD16 + cells [3] and decreased cytotoxic activity of NK cells [4].…”

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

“…1 Natural killer (NK) cells, lymphocytes of the innate immune system, are considered to be a major component of the immunosurveillance in leukemia. [2][3][4] However, little is known about the functionality of NK cells and their role in tumor immune escape in CLL.…”

“…1 Natural killer (NK) cells, lymphocytes of the innate immune system, are considered to be a major component of the immunosurveillance in leukemia. [2][3][4] However, little is known about the functionality of NK cells and their role in tumor immune escape in CLL.NK cells are tightly regulated by inhibitory or activating "missing self" and "induced self" signals sensed via cell surface receptors. 5 The best examined activating receptors are the Fc receptor CD16, NKG2D, and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46.…”