CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

S Su, Z Zou, F Chen, N Ding, J Du, J Shao, L Li… - …, 2017 - Taylor & Francis
S Su, Z Zou, F Chen, N Ding, J Du, J Shao, L Li, Y Fu, B Hu, Y Yang, H Sha, F Meng, J Wei…
Oncoimmunology, 2017Taylor & Francis
The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y
has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-
associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high
amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr
virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1
pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC. These studies …
Abstract
The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1 pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC. These studies reveal possibility of generating PD-1-disrupted CTL by CRISPR-Cas9 system and demonstrate enhanced immune response of these PD-1-disrupted CTLs to the EBV-LMP2A antigen and superior cytotoxicity to the EBV-positive gastric cancer cell. In addition, when combined with low-dose radiotherapy, these PD-1-disrupted CTLs mediated an impressive antitumor effect in a xenograft mouse model of EBVaGC. Taken together, these studies illustrate PD-1/PD-L1-mediated immune tolerance of EBVaGC and provide a new strategy for targeting immune checkpoints to break the tolerance for the T cell-based adoptive therapy.
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