Imunoterapia: acesso aberto
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Overview of the Soluble and Membrane-bound Tumor Factors Limiting NK-mediated Immune Surveillance

Cristina Bottino, Mariella Della Chiesa, Alessandra Dondero*, Francesca Bellora, Beatrice Casu, Alessandro Moretta and Roberta Castriconi

Many evidences suggest that NK cells are effective in patrolling for and eliminating tumors in their onset phase, but hardly limit the progression of large established solid tumors. Beside the transition of tumor cells towards a more aggressive phenotype, the NK cell efficacy might be limited by a complex immunosuppressive milieu present in the tumor microenvironment. Indeed, different mechanisms damping NK cell function have been shown in these last years. These include a plethora of tumor-derived immunomodulatory soluble factors (TGF-β, MIF, adenosine, L-Kynurenin, PGE2) as well as soluble ligands (MICA, ULBP-2, PVR, B7-H6) that compete with membrane-bound tumor ligands for binding to activating NK receptors. During NK-tumor cell contact the NK cell function can also be inhibited by the engagement on NK cells of different inhibitory receptors. The specific ligands might be either constitutively expressed at the tumor cell surface (HLA-I, B7-H3, PVR) or de novo induced/up-regulated (PD-Ls) by immunostimulatory factors (IFN-γ, TNF-α). These are largely released during the active phases of the immune responses and exert an unwonted side effect called “tumor adaptive immune resistance”. This review aims to summarize the best-known molecular mechanisms that, at various times and in different ways, can limit the efficacy of the NK-mediated immune surveillance of tumors.