Abstract
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.
Highlights
Natural killer cells (NK) are crucial cytolytic effectors belonging to the family of innate lymphoid cell (ILC) [1,2]
This review summarizes the best-known tumorderived soluble factors and tumor-associated surface molecules exerting an immunomodulatory role in NK cells
NK cell-based immunotherapy is becoming a promising approach for the treatment of both hematological malignances and solid tumors
Summary
Natural killer cells (NK) are crucial cytolytic effectors belonging to the family of innate lymphoid cell (ILC) [1,2]. Overall data suggest that TGF-β1 antagonists, capable of overcoming or blocking its immunomodulatory effect might represent a valuable adjuvant therapy in the cure of different tumors In this context, it has been recently shown that blocking of TGF-β1R in combination with antibodies targeting the NB-associated antigen GD2, potentiates the NK-mediated anti-NB activity leading to a reduced tumor growth and increased survival of mice injected with NB cell lines or patient-derived neuroblasts [56]. Since studies explored the cytokine-induced expression of these coinhibitory receptors mainly in long term-cultured NK cell lines such as NK92 [93], data on primary NK cells are required to better understand the relative contribution of these inhibitory pathways and the kinetic that regulates their emergence Another interesting NK-to-tumor contact inhibitory pathway is mediated by the B7-H3 ligand, a tumor-associated surface molecule, present in tumor-derived exosomes [94], which is endowed with both immune-regulatory and pro-tumoral functions. In primary neuroblastoma high B7-H3 surface expression, in terms of both intensity and percentage of positive cells, has been correlated with poor event-free survival in patients with localized disease (stage 1–3), suggesting that high B7-H3 expression might discriminate between low- and high-risk patients who need a more careful follow-up
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