Inhibition of neuroblastoma cell growth by TREX1-mutated human lymphocytes

Abstract

T lymphocytes play a major role in counteracting cancer occurrence and development. Immune therapies against cancer are focused on eliciting a cytotoxic Tcell response. This anticancer activity is related to a variety of mechanisms including the activation of cytokines and proapoptotic mediators. Interferonα is an established inhibitor of cancer cell growth. A clinical situation involving the coexistence of high interferonα levels and lymphocyte activation is the Aicardi-Goutières syndrome, a progressive encephalopathy arising usually during the first year of life characterized by intracranial basal ganglia calcifications, leukodystrophy and microcephaly. Aicardi-Goutières syndrome1 mutation silences the TREX1 gene, a major endogenous nuclease. The invitro study presented herein evaluates the efficacy of the TREX1 mutation in potentiating the anticancer properties of Tcells. A TREX1-mutated lymphocyte cell line was derived from an Aicardi-Goutières syndrome patient and co-cultured with neuroblastoma cells and vascular endothelial cells in the presence of interferonα. TREX1-mutated lymphocytes exerted marked inhibitory action on neuroblastoma cell growth. CathepsinD was recognized by qPCR as the main mediator produced by TREX1-mutated lymphocytes involved in the inhibition of neuroblastoma cell growth. These effects were enhanced in the presence of interferonα. Similar inhibitory effects in cell growth were exerted by TREX1-mutated lymphocytes towards vascular endothelial cell angiogenesis as evaluated on Matrigel. The results obtained provide evidence that mutations of the TREX1 gene increase the capability of T-lymphocytes to inhibit growth of neoplastic neuronal cells and related angiogenesis.