The added value of natural killer cells in immunotherapy for leukemia.

摘要

The observation that the immune system can recognize and eliminate tumors is the impetus of the fast-growing domain of tumor immunology and the development of therapeutic tumor vaccination strategies. While current standard therapies for acute myeloid leukemia (AML) can successfully induce remission, the disease is characterized by a high probability of relapse and refractory disease due to the persistence of residual leukemic cells. Immunotherapy for leukemia is a promising targeted strategy to prevent relapse and to prolong the survival of leukemia patients.;Active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells and to generate a potent lasting antitumor response. In this regard, there is strong interest in simultaneous targeting of multiple immune cells of the host's antitumor immunity on one hand and the immunogenic properties of the tumor cell compartment on the other hand. In particular the concomitant activation of dendritic cells (DC) and natural killer (NK) cells -- respectively the orchestrators of cellular immunity and the key players of innate immunity -- is currently an attractive modality for immune-based therapies. When targeting the tumor, the aim is to induce immunogenic cell death to break immune tolerance against tumor cells and to facilitate their recognition as malign cells by neighboring immune cells. In immunotherapy, there is a reinvigorated interest in NK cells for their direct cytotoxic and immunoregulatory capacity and their recently acknowledged indirect contribution to tumor control. By communicating with DC (i.e. NK-DC cross-talk) and other immune cells, NK cells have been shown to support the development of an efficient adaptive antitumor immune response.;In this thesis, the primary scope was to increase the immunogenicity of AML cells by introducing a danger signal to break immune tolerance. We clearly demonstrate that electroporation of AML cells with the danger signal poly(I:C) provides a way to overcome immune evasion, evidenced by their enhanced capacity to activate NK cell and DC functions and stimulate NK-DC cross-talk. We draw particular attention to the significance of NK cells, advocating for reinforcement of both cytotoxic and regulatory NK cell functions in cancer immunotherapy and detecting these functions in immunomonitoring approaches.