The prognosis of high-risk neuroblastoma (NB) remains poor, although immunotherapies with anti-GD2 antibodies have been reported to provide some benefit. Immunotherapies can be associated with an IFNγ storm that induces in tumor cells the “adaptive immune resistance” characterized by the de-novo expression of Programmed Death Ligands (PD-Ls). Tumor cells can also constitutively express PD-Ls in response to oncogenic signaling. Here, we analyze the constitutive and the inducible surface expression of PD-Ls in NB cells. We show that virtually all HLA class Ipos NB cell lines constitutively express PD-L1, whereas PD-L2 is rarely detected. IFNγ upregulates or induces PD-L1 both in NB cell lines in vitro and in NB engrafted nude/nude mice. Importantly, after IFNγ stimulation PD-L1 can be acquired by NB cell lines, as well as by metastatic neuroblasts isolated from bone marrow aspirates of high-risk NB patients, characterized by different MYCN amplification status. Interestingly, in one patient NB cells were poorly responsive to IFNγ stimulation, pointing out that responsiveness to IFNγ might represent a further element of heterogeneity in metastatic neuroblasts. Finally, we document the presence of lymphocytes expressing the PD-1 receptor in NB-infiltrated bone marrow of patients. PD-1pos cells are mainly represented by αβ T cells, but also include small populations of γδ T cells and NK cells. Moreover, PD-1pos T cells have a higher expression of activation markers. Overall, our data show that a PD-L1-mediated immune resistance mechanism occurs in metastatic neuroblasts and provide a biological rationale for blocking the PD-1/PD-Ls axis in future combined immunotherapeutic approaches.

Dondero, A., Pastorino, F., Della Chiesa, M., Corrias, M. V., Morandi, F., Pistoia, V., Olive, D., Bellora, F., Locatelli, F., Castellano, A., Moretta, L., Moretta, A., Bottino, C., Castriconi, R., PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance, <<ONCOIMMUNOLOGY>>, 2016; 5 (1): e1064578-1-e1064578-9. [doi:10.1080/2162402X.2015.1064578] [https://hdl.handle.net/10807/229907]

PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance

Locatelli, Franco
Writing – Review & Editing
;
2016

Abstract

The prognosis of high-risk neuroblastoma (NB) remains poor, although immunotherapies with anti-GD2 antibodies have been reported to provide some benefit. Immunotherapies can be associated with an IFNγ storm that induces in tumor cells the “adaptive immune resistance” characterized by the de-novo expression of Programmed Death Ligands (PD-Ls). Tumor cells can also constitutively express PD-Ls in response to oncogenic signaling. Here, we analyze the constitutive and the inducible surface expression of PD-Ls in NB cells. We show that virtually all HLA class Ipos NB cell lines constitutively express PD-L1, whereas PD-L2 is rarely detected. IFNγ upregulates or induces PD-L1 both in NB cell lines in vitro and in NB engrafted nude/nude mice. Importantly, after IFNγ stimulation PD-L1 can be acquired by NB cell lines, as well as by metastatic neuroblasts isolated from bone marrow aspirates of high-risk NB patients, characterized by different MYCN amplification status. Interestingly, in one patient NB cells were poorly responsive to IFNγ stimulation, pointing out that responsiveness to IFNγ might represent a further element of heterogeneity in metastatic neuroblasts. Finally, we document the presence of lymphocytes expressing the PD-1 receptor in NB-infiltrated bone marrow of patients. PD-1pos cells are mainly represented by αβ T cells, but also include small populations of γδ T cells and NK cells. Moreover, PD-1pos T cells have a higher expression of activation markers. Overall, our data show that a PD-L1-mediated immune resistance mechanism occurs in metastatic neuroblasts and provide a biological rationale for blocking the PD-1/PD-Ls axis in future combined immunotherapeutic approaches.
2016
Inglese
Dondero, A., Pastorino, F., Della Chiesa, M., Corrias, M. V., Morandi, F., Pistoia, V., Olive, D., Bellora, F., Locatelli, F., Castellano, A., Moretta, L., Moretta, A., Bottino, C., Castriconi, R., PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance, <<ONCOIMMUNOLOGY>>, 2016; 5 (1): e1064578-1-e1064578-9. [doi:10.1080/2162402X.2015.1064578] [https://hdl.handle.net/10807/229907]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/229907
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