Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of 9%. Major obstacles to successful treatment of pancreatic cancer are the immunosuppressive tumor microenvironment (TME) and antigenic complexity or heterogeneity. Programmed death-ligand 1 (PD-L1) is expressed on PDAC and immunosuppressed cells within the TME, providing suitable immunotherapy targets. We applied a chimeric antigen receptor (CAR) strategy to target immune checkpoint programmed death-1 (PD-1)/PD-L1 interactions. Lentiviral vectors were used to express the extracellular domain of human PD-1 (PD-1-CD28-4-1BB activating chimeric receptor [PD1ACR]) or the single-chain variable fragment (scFv) region of anti-PD-L1 (PDL1CAR) that binds to PD-L1, and each was fused to intracellular signaling domains containing CD3 zeta, CD28, and 4-1BB (CD137). Both engineered CAR T cells recognized and eliminated PD-L1-overexpressing CFPAC1 cells efficiently at approximately 80% in vitro. Adoptive transfer of both CAR T cells enhanced T cell persistence and induced specific regression of established CFPAC1 cancer by >80% in both xenograft and orthotopic models. Ki67 expression in tumors decreased, whereas proinflammatory cytokines/chemokines increased in CAR T cell-treated mouse sera. PD1ACR and PDL1CAR obtained a similar therapeutic efficacy. Thus, these armed third-generation PD-L1-targeted CAR T cells confer antitumor activity and the ability to combat T cell exhaustion, providing a potentially new and innovative CAR T cell immunotherapy against pancreatic cancers.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and intractable human malignant tumors and a leading cause of cancer-related deaths worldwide.[1,2] Patients with PDAC have a median survival rate of 5 months after diagnosis, and the overall 5-year survival rate is
The expression of activating chimeric receptor (ACR) and chimeric antigen receptor (CAR) in transduced T cells was demonstrated through programmed death-1 (PD-1) and aPDL1 expressions by using anti-PD-1 and anti-human immunoglobulin G (IgG), respectively
We developed programmed death-1 ligand-1 (PD-L1)-targeted ACR/CAR T cells by using third-generation CARs containing additional signaling domains, including CD28, CD137, and OX40.23,24 Both types of PD-L1-targeted ACR/CAR T cells could destroy pancreatic cancers (PaCs) cell-associated PD-L1 in vitro and in the tumor xenograft/orthotopic mouse models
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and intractable human malignant tumors and a leading cause of cancer-related deaths (estimated 7.3% in 2018) worldwide.[1,2] Patients with PDAC have a median survival rate of 5 months after diagnosis, and the overall 5-year survival rate is
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