Phagocyte-induced apoptosis in natural killer cells and T cells. Role of reactive oxygen species and regulation by histamine

Abstract: Malignant tumors frequently contain an infiltrate of leukocytes, usually cells of the monocyte/macrophage lineage and lymphocytes with anti-tumor activity such as natural killer (NK) cells and T cells. Clinical and experimental data suggest that monocytes/macrophages in tumors inhibit functions of adjacent NK cells/T cells and thereby suppress lymphocyte-dependent anti-tumor immunity. Recently, much attention has been focused on the capacity of monocytes/macrophages to generate reactive oxygen species, which are toxic for many cells ('oxidative stress'), as a mechanism contributing to the state of immunosuppression in malignant tumors.In this thesis, the function and fate of human NK cells and T cells were studied in vitro in a reconstituted environment of oxidative stress inflicted by monocyte-derived reactive oxygen species, aimed at mimicking the microenvironment in malignant tumors. It is reported that monocytes inhibit NK cell functions, including the cytotoxicity against tumor cells and cytokine gene transcription and production, and that monocytes also inhibit the activation of NK cells and T cells induced by interleukin-2 (IL-2). In addition, monocytes induced suicidal cell death (apoptosis) in a significant fraction of NK cells and T cells. The monocyte-induced suppression and apoptosis were triggered by reactive oxygen species and mimicked by other phagocytes such as neutrophilic granulocytes. It is further shown that malignant granulocytes, recovered from patients with chronic myelogenous leukemia (CML), inhibit NK cell cytotoxicity and induce apoptosis in NK cells and in T cells. As was the case for non-malignant granulocytes, the CML cell-induced suppression of NK cells and T cells was mediated by reactive oxygen species. Anti-oxidative agents such as histamine, diphenylene iodonium, and catalase were found to protect NK cells and T cells from phagocyte-induced apoptosis and functional inhibition. The results may shed further light on the mechanisms by which malignant tumors escape anti-tumor immunity. Revealing and understanding these mechanisms and their regulation may form a basis for improved immunotherapy of neoplastic diseases.