title: Natural killer cells and neuroblastoma: tumor recognition, escape mechanisms, and possible novel immunotherapeutic approaches.
abstract: Neuroblastoma (NB) is the most common extra-cranial solid tumor of childhood and arises from developing sympathetic nervous system. Most primary tumors localize in the abdomen, the adrenal gland, or lumbar sympathetic ganglia. Amplification in tumor cells of MYCN, the major oncogenic driver, patients' age over 18 months, and the presence at diagnosis of a metastatic disease (stage IV, M) identify NB at high risk of treatment failure. Conventional therapies did not significantly improve the overall survival of these patients. Moreover, the limited landscape of somatic mutations detected in NB is hampering the development of novel pharmacological approaches. Major efforts aim to identify novel NB-associated surface molecules that activate immune responses and/or direct drugs to tumor cells and tumor-associated vessels. PVR (Poliovirus Receptor) and B7-H3 are promising targets, since they are expressed by most high-risk NB, are upregulated in tumor vasculature and are essential for tumor survival/invasiveness. PVR is a ligand of DNAM-1 activating receptor that triggers the cytolytic activity of natural killer (NK) cells against NB. In animal models, targeting of PVR with an attenuated oncolytic poliovirus induced tumor regression and elimination. Also B7-H3 was successfully targeted in preclinical studies and is now being tested in phase I/II clinical trials. B7-H3 down-regulates NK cytotoxicity, providing NB with a mechanism of escape from immune response. The immunosuppressive potential of NB can be enhanced by the release of soluble factors that impair NK cell function and/or recruitment. Among these, TGF-β1 modulates the cytotoxicity receptors and the chemokine receptor repertoire of NK cells. Here, we summarize the current knowledge on the main cell surface molecules and soluble mediators that modulate the function of NK cells in NB, considering the pros and cons that must be taken into account in the design of novel NK cell-based immunotherapeutic approaches.
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova , Genova , Italy ; Istituto Giannina Gaslini , Genova , Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottino
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova , Genova , Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dondero
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova , Genova , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bellora
authors.affiliation: Istituto Giannina Gaslini , Genova , Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Dipartimento di Onco-Ematologia Pediatrica, Ospedale Bambino Gesù , Roma , Italy ; Università di Pavia , Pavia , Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Istituto Giannina Gaslini , Genova , Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova , Genova , Italy ; Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova , Genova , Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova , Genova , Italy ; Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova , Genova , Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Castriconi
keywords: B7-H3; PVR; TGF-beta; chemokine receptors; immunotherapeutic approaches; natural killer cells; neuroblastoma; tumor escape mechanisms