Immunotherapy and immunosuppression in myeloid leukemia

Abstract

Acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) are potentially life-threatening blood cancers characterized by the expansion of malignant myeloid cells in bone marrow and other organs. This thesis aimed at contributing to the understanding of the role of natural killer (NK) cells in AML and CMML with focus on the potential impact of the immunosuppression exerted by reactive oxygen species (ROS) formed by the myeloid cell NOX2 enzyme. The thesis work has comprised in vitro studies of interactions between NK cells and primary myeloid leukemic cells along with analyses of NK cell repertoires in a clinical trial using a NOX2 inhibitor, histamine dihydrochloride (HDC) in conjunction with the NK cell-activating cytokine interleukin-2 (IL-2) for the prevention of relapse of AML after the completion of chemotherapy. Paper I reports that the functions and viability of cytotoxic lymphocytes, including NK cells, were compromised by ROS produced by leukemic myeloid cells recovered from patients with CMML. The results are thus suggestive of a novel mechanism of leukemia-induced immunosuppression in this disease. Paper II analyzed aspects of myeloid cell populations in AML using blood samples from a clinical phase IV trial where AML patients (n=84) received HDC in conjunction with IL-2. The results imply that HDC may exert anti-leukemic efficacy by facilitating the maturation of myeloid cells, which impacts on the efficiency of immunotherapy with HDC/IL-2. In papers III and IV we explored the role of killer cell immunoglobulin-like receptors (KIR) for the relapse and survival of AML patients receiving HDC/IL-2. The results suggest that a subset of immature NK cells with low KIR expression may determine clinical outcome. In paper IV we further analyzed results from the above-referenced phase IV trial and observed that a past cytomegalovirus (CMV) infection predicted high relapse risk and poor survival, presumably by reducing the pool of immature NK cells. The results of paper V suggest that a dimorphism in the leader peptide of HLA-B is relevant to NK cell-mediated killing of AML cells and to the outcome of immunotherapy. In conclusion, this thesis work presents novel aspects of myeloid cell-induced immunosuppression in AML and CMML and identifies NK cell subsets of potential relevance to the benefit of immunotherapy with HDC/IL-2.