GD2-CAR NK-92 cell activity against neuroblastoma cells is insusceptible to TIGIT knockout.
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Immunotherapy by inhibition of immune checkpoint (IC) molecules has emerged as an important cancer therapy. Among these lC, the poliovirus receptor/poliovirus receptor-like 2 protein (PVR/PVRL2)-TIGIT axis was discovered as potential target for various cancers. For neuroblastoma (NB), the most common extracranial solid cancer in children, no effective IC therapy has been established yet. To investigate the PVR/PVRL2-TIGIT IC axis as a new target for the treatment of NB, we analysed whether PVR and PVRL2 influence the survival of patients and verified the expression of the receptors on NB cell lines. To disrupt the checkpoint axis, we performed single and double knockouts of these receptors on NB cell lines and subsequently removed TIGIT, an inhibitory receptor on immune effector cells, from NK-92 cells. Finally, we combined checkpoint inhibition with GD2-CAR NK-92 cells and investigated changes in cytotoxicity. Using RNA-Seq data we showed that the expression of PVR and PVRL2 on NB cells correlates to a lower event-free survival of patients. CRISPR/Cas9 knockouts of PVR and PVRL2 showed no improved cytotoxic activity of NK-92 cells. We observed enhanced lysis of NB cells using TIGIT-deficient NK-92 cells. However, the cytotoxicity of GD2-CAR NK-92 was not significantly enhanced. In summary, we have shown that in addition to the interaction of PVR/PVRL2 and TIGIT on engineered immune effector cells against NB, pleiotropic ligands appear to be relevant. Deletion of TIGIT from immune effector cells is a promising approach to protect these cells from tumour-associated inhibitory signals but cannot enhance the effect of GD2-CAR-NK-92 cells.