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    • Target cell availability is probably

    2018-10-25

    Target cell availability is probably maximal for NK erk inhibitor in blood borne cancers, hence, we believe that these diseases will show the highest CD45RARO NK cell numbers; although these cells are unable to control the disease. Leukemogenesis in mouse is enhanced when the host immune system is impaired (Garaude et al., 2008; Kaminski et al., 2012) and more hematological cancer patients present severe NK cell dysfunctions (Baier et al., 2013). Others and we have shown the requirement of fully functional NK cells to eradicate blood-borne tumors in several mouse models (Karre et al., 1986; van den Broek et al., 1995; Pardo et al., 2002; Aguilo et al., 2009; Charni et al., 2009; Charni et al., 2010; Ramírez-Comet et al., 2014). The use of alloreactive NK cells may represent a new cancer treatment, specifically for tumors of hematopoietic origin. Indeed, KIR–KIR ligand incompatibility in the graft-versus-host (GvH) direction, which is mainly based on NK cell alloreactivity, improves the outcome after unrelated cord blood stem cell transplantation (UCBT) in the clinic (Willemze et al., 2009; Stern et al., 2008). Moreover, NK cells: i) are not responsible of GvH disease (GvHD); ii) can be injected as “differentiated” cells and thus do not need to survive within the patient\'s body for a long time; iii) protect from opportunistic infections (Willemze et al., 2009), probably through their immunoregulatory effects on B and T cells, macrophages and, more importantly, polymorphonuclear cells (Bhatnagar et al., 2010). However, evaluation of NK cell activation in vivo is difficult because we lack effective methods for their analysis. CD69 expression has routinely been used (Elpek et al., 2010; Vey et al., 2012); though, our results show that CD69 expression does not imply degranulation, which is believed to be the most essential component of the NK cell anti-tumor activity (Bryceson et al., 2011), or trogocytosis. Conversely, our work indicates that CD45RO expression identifies degranulating NK cell subsets in patients with hematological malignancies. We believe that efficient antitumor treatments that involve also NK cell activity, such as monoclonal antibodies against tumor antigens, should also increase these NK cell populations. Other options for treatment include new chemicals that can be associated with immunotherapy to boost the immune response (Villalba et al., 2014) and that could improve the NK cell-mediated response (Catalán et al., 2015). CD45 activity is regulated by dimerization and spontaneous CD45 homodimerization at the plasma membrane inhibits its activity (Xu and Weiss, 2002). The size of CD45 extracellular domain is inversely proportional to the extent of CD45 dimerization and thus self-inhibition (Xu and Weiss, 2002). Larger CD45 isoforms, such as CD45RA, dimerize less efficiently and, accordingly, they should better promote TCR signaling than smaller isoforms, such as CD45RO (Rhee and Veillette, 2012). However, CD45 activity also depends on its plasma membrane localization and thus on its extracellular domain (Mustelin et al., 2005; Rhee and Veillette, 2012). At least in T cells, too high CD45 activity leads to dephosphorylation of the activating residues in Src kinases, whereas too low CD45 activity might leave phosphorylated the inhibitory residues. Therefore, it is important for efficient NK cell activation that CD45 activity remains within a specific window (Hermiston et al., 2009) and the amount of specific CD45 isoforms will regulate the final activity. We found that CD45RARO NK cells show maximal degranulation and trogocytosis, suggesting that expression of both CD45RA and CD45RO isoforms might give to NK cells the appropriate level of CD45 activity for efficient signaling to boost cytotoxicity. CD45 is required for full NK cell cytotoxicity in vivo in mice (Hesslein et al., 2011); however, it is not required in vitro (Mason et al., 2006; Hesslein et al., 2006; Huntington et al., 2005). In agreement, we observed that other NK cell subsets, which express different CD45 isoforms, improved degranulation in vitro. This suggests that NK cells depend less of CD45 expression in vitro than in vivo.