Mechanisms influencing natural killer cell recognition of tumour cells

University dissertation from Stockholm : Karolinska Institutet, Dept of Medicine, Huddinge

Abstract: Natural killer (NK) cells are part of our innate immune defence against virus-infected and transformed cells. Through a yet undefined mechanism, expression of inhibitory receptors for self-HLA class I molecules endow NK cells with increased functionality. The process leading to gain of function through inhibition is known as NK cell education. In the first part of this thesis the cellular mechanisms behind this phenomenon were studied. We found that the expression levels of the activation/adhesion molecule DNAM-1 correlated with the education state in NK cells. Our results suggest that DNAM-1 together with coordinated conformational changes in the adhesion molecule LFA-1 may contribute to the heightened effector functions in educated NK cells. A decreased NK cell function has been previously associated with impaired immune surveillance and a higher risk for developing cancer. By studying samples from patients diagnosed with myelodysplastic syndromes (MDS), we found that NK cells in the bone marrow were phenotypically altered and functionally impaired. Two activating receptors, DNAM-1 and NKG2D were decreased, and the ability to recognise and kill MDS blast cells compromised. The phenotypic alterations correlated with the frequency of leukemic blast cells suggesting that the immune dysfunction progress with the severity of the disease. In one part of this thesis possibilities to improve tumour cell recognition by NK cells were examined. Oxidative stress induced by selenite in a tumour cell line lowered the surface expression of HLA-E, which is a ligand for inhibitory NKG2A receptors expressed by a large proportion of human NK cells. The downregulation of HLA-E led to increased NK cell detection and killing of the tumour cells by NKG2A+ NK cells. Therapeutic antibodies have led to a paradigm shift in the care of patients with malignant lymphoma. Yet the mechanisms of action and the contribution of discrete immune subsets to the clinical efficacy are largely unknown. One suggested mechanism is NK cell mediated antibody-dependent cellular cytotoxicity. We studied NK cell repertoires in sequential lymph node biopsies from follicular lymphoma patients undergoing treatment with anti-CD20 antibodies. After treatment there was a decrease in peripheral NK cells, and the remaining NK cells from both peripheral blood and tumour-associated lymph nodes were activated. Furthermore, the NK cells showed an altered ability to produce cytokines after in vitro restimulation. In conclusion, the data presented here provide new insights into how NK cells recognise and respond to tumour cells at steady state and in malignant diseases.

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