Limits...
Natural killer cells and neuroblastoma: tumor recognition, escape mechanisms, and possible novel immunotherapeutic approaches.

Bottino C, Dondero A, Bellora F, Moretta L, Locatelli F, Pistoia V, Moretta A, Castriconi R - Front Immunol (2014)

Bottom Line: PVR is a ligand of DNAM-1 activating receptor that triggers the cytolytic activity of natural killer (NK) cells against NB.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.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova , Genova , Italy ; Istituto Giannina Gaslini , Genova , Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Inhibitory and activating interactions between human NK cells and neuroblasts. NB express ligands that are recognized by NK receptors with activating or inhibitory function. While DNAM-1/PVR interactions play a pivotal role in triggering NK cell-mediated killing, B7-H3 dampens NK cell function. NB usually lack or express low, non-protective levels of HLA class I molecules. However, therapeutic approaches such as the in vivo administration of anti-GD2 Abs could induce not only ADCC of NB but also the release of INF-γ, which upregulates the expression of the ligands for inhibitory KIR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3921882&req=5

Figure 1: Inhibitory and activating interactions between human NK cells and neuroblasts. NB express ligands that are recognized by NK receptors with activating or inhibitory function. While DNAM-1/PVR interactions play a pivotal role in triggering NK cell-mediated killing, B7-H3 dampens NK cell function. NB usually lack or express low, non-protective levels of HLA class I molecules. However, therapeutic approaches such as the in vivo administration of anti-GD2 Abs could induce not only ADCC of NB but also the release of INF-γ, which upregulates the expression of the ligands for inhibitory KIR.

Mentions: In NB, initial data were obtained by the use, as target cells, of in vitro established NB cell lines (39). NK cells displayed strong cytolytic activity against different NB cells and NCR were involved in the mechanisms leading to killing (39). The susceptibility of human NB cell lines to NK-mediated killing was validated in the context of a metastatic model set up in NOD/SCID mice. In this experimental setting, repeated infusions of IL-2 or IL-15 activated NK cells resulted in both an increased mean survival time of HTLA-230-bearing mice and reduced BM infiltration (40). Considering that long term cultured cell lines might be poorly representative of original tumors, more interesting data originated from in vitro studies that use neuroblasts, freshly purified from BM aspirate of stage 4 patients (36) (Figures 1 and 2). In this study, allogeneic activated NK cells killed neuroblasts isolated from patients although at a lesser extent as compared to the NB cell lines used as control. According to the absence or negligible expression of HLA class I molecules, the NK-mediated lysis of neuroblasts did not increase in the presence of anti-HLA class I mAb. Different molecular mechanisms responsible for the reduced HLA class I expression in NB cells have been elucidated. The immunohistochemical analysis of high-risk human NB showed different abnormalities in the antigen processing machinery, which include defects in the expression of immunoproteasomal subunits LMP2 and LMP7 and of transporters of antigen processing (TAP) (37). In vitro treatment of NB cells with IFN-γ induced up-regulation of HLA class I expression (37). Although decreasing their susceptibility to autologous NK cells, this up-regulation of HLA class I molecules could enhance T cell-mediated recognition. In this context, a restoration of killing mediated by antigen specific (MAGE3) cytolytic T cells was observed upon cotransfection of NB cell lines with IRF1 and NF-kB p65, HLA class I transcriptional activators that are also induced by INFγ and TNFα, respectively (41). It cannot be excluded that also in vivo neuroblasts could acquire/upregulate HLA class I expression. For example, this might occur in the context of transplantation or following the anti-GD2 antibody-mediated therapy that engages FcγR+ immune cells such as NK cells, which are capable of releasing high amounts of IFN-γ upon activation (Figure 1). This phenomenon was observed in a murine NB model, where recurrent tumors developed after an NK-dependent anti-tumor response induced by a humanized IL-2 immunocytokine targeted to GD2. In these mice, NB cells showed markedly enhanced MHC class I expression as compared with tumors growing in controls (42). The possible in vivo increase of HLA class I expression in NB cells could explain the benefit of a KIR/KIR-L mismatch in the NK versus NB direction (43–45).


Natural killer cells and neuroblastoma: tumor recognition, escape mechanisms, and possible novel immunotherapeutic approaches.

Bottino C, Dondero A, Bellora F, Moretta L, Locatelli F, Pistoia V, Moretta A, Castriconi R - Front Immunol (2014)

Inhibitory and activating interactions between human NK cells and neuroblasts. NB express ligands that are recognized by NK receptors with activating or inhibitory function. While DNAM-1/PVR interactions play a pivotal role in triggering NK cell-mediated killing, B7-H3 dampens NK cell function. NB usually lack or express low, non-protective levels of HLA class I molecules. However, therapeutic approaches such as the in vivo administration of anti-GD2 Abs could induce not only ADCC of NB but also the release of INF-γ, which upregulates the expression of the ligands for inhibitory KIR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921882&req=5

Figure 1: Inhibitory and activating interactions between human NK cells and neuroblasts. NB express ligands that are recognized by NK receptors with activating or inhibitory function. While DNAM-1/PVR interactions play a pivotal role in triggering NK cell-mediated killing, B7-H3 dampens NK cell function. NB usually lack or express low, non-protective levels of HLA class I molecules. However, therapeutic approaches such as the in vivo administration of anti-GD2 Abs could induce not only ADCC of NB but also the release of INF-γ, which upregulates the expression of the ligands for inhibitory KIR.
Mentions: In NB, initial data were obtained by the use, as target cells, of in vitro established NB cell lines (39). NK cells displayed strong cytolytic activity against different NB cells and NCR were involved in the mechanisms leading to killing (39). The susceptibility of human NB cell lines to NK-mediated killing was validated in the context of a metastatic model set up in NOD/SCID mice. In this experimental setting, repeated infusions of IL-2 or IL-15 activated NK cells resulted in both an increased mean survival time of HTLA-230-bearing mice and reduced BM infiltration (40). Considering that long term cultured cell lines might be poorly representative of original tumors, more interesting data originated from in vitro studies that use neuroblasts, freshly purified from BM aspirate of stage 4 patients (36) (Figures 1 and 2). In this study, allogeneic activated NK cells killed neuroblasts isolated from patients although at a lesser extent as compared to the NB cell lines used as control. According to the absence or negligible expression of HLA class I molecules, the NK-mediated lysis of neuroblasts did not increase in the presence of anti-HLA class I mAb. Different molecular mechanisms responsible for the reduced HLA class I expression in NB cells have been elucidated. The immunohistochemical analysis of high-risk human NB showed different abnormalities in the antigen processing machinery, which include defects in the expression of immunoproteasomal subunits LMP2 and LMP7 and of transporters of antigen processing (TAP) (37). In vitro treatment of NB cells with IFN-γ induced up-regulation of HLA class I expression (37). Although decreasing their susceptibility to autologous NK cells, this up-regulation of HLA class I molecules could enhance T cell-mediated recognition. In this context, a restoration of killing mediated by antigen specific (MAGE3) cytolytic T cells was observed upon cotransfection of NB cell lines with IRF1 and NF-kB p65, HLA class I transcriptional activators that are also induced by INFγ and TNFα, respectively (41). It cannot be excluded that also in vivo neuroblasts could acquire/upregulate HLA class I expression. For example, this might occur in the context of transplantation or following the anti-GD2 antibody-mediated therapy that engages FcγR+ immune cells such as NK cells, which are capable of releasing high amounts of IFN-γ upon activation (Figure 1). This phenomenon was observed in a murine NB model, where recurrent tumors developed after an NK-dependent anti-tumor response induced by a humanized IL-2 immunocytokine targeted to GD2. In these mice, NB cells showed markedly enhanced MHC class I expression as compared with tumors growing in controls (42). The possible in vivo increase of HLA class I expression in NB cells could explain the benefit of a KIR/KIR-L mismatch in the NK versus NB direction (43–45).

Bottom Line: PVR is a ligand of DNAM-1 activating receptor that triggers the cytolytic activity of natural killer (NK) cells against NB.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.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova , Genova , Italy ; Istituto Giannina Gaslini , Genova , Italy.

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.

No MeSH data available.


Related in: MedlinePlus