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Immune Suppression in Multiple Myeloma

其他書名	Strategies to Overcome NK Cell Inhibition
出版	King's College, London, 2013
URL	http://books.google.com.hk/books?id=cXJ4jwEACAAJ&hl=&source=gbs_api

註釋Multiple myeloma (MM) is an essentially incurable malignancy associated with profound cellular and soluble immune deficiencies. Despite recent progresses in the treatment of MM, the prognosis remains frequently poor due to the difficulty in targeting MM progenitor cells, which are responsible for disease relapse. Immunotherapy, and in particular the employment of Natural Killer (NK) cells, offers the potential to target and eliminate MM cells within the bone marrow stromal sanctuaries, where they appear to be better protected against conventional therapeutic interventions. However, these strategies have so far provided limited clinical benefit, possibly reflecting the various escape mechanisms employed by MM cells to avoid immune recognition. The work presented in this thesis aims to further elucidate the mechanisms underlying MM-induced inhibition of NK cells and to investigate the therapeutic potential of immunomodulatory strategies to reverse this inhibition. Initially, the effect of co-culturing MM cell lines and healthy donor (HD) peripheral blood mononuclear cells (PBMCs) on NK cell phenotype and function was analysed. The results demonstrate that MM cell lines are able to impair NK cell cytolytic activity. This inhibition, which correlates with the downregulation of activating receptors such as NKG2D, NKp30, and DNAM-1, was shown to be the product of direct and contactdependent interactions between MM and NK cells, without the need for other peripheral blood components. Importantly, the analysis of NK cells isolated from MM patients show that they display the same suppressed phenotype and activity as healthy donor NK cells co-cultured in the presence of MM cells lines, thereby suggesting that the detected suppression of NK cell activation by MM cells is a function of MM cells rather than any inherent defect in NK cells isolated from MM patients.