J Cancer 2019; 10(11):2578-2587. doi:10.7150/jca.26961

Research Paper

Blocking the PD-1/PD-L1 axis in dendritic cell-stimulated Cytokine-Induced Killer Cells with pembrolizumab enhances their therapeutic effects against hepatocellular carcinoma

Wan Zhang1,2,*, Zhenghui Song1,2,*, Jianpeng Xiao1,2, Xinhui Liu1,2,3, Yue Luo1,2, Zike Yang1,2, Rongcheng Luo1,2✉, Aimin Li1,2,3✉

1. Integrated Hospital of Traditional Chinese Medicine, Southern Medical University Guangzhou, 510315, China
2. Cancer Center, Southern Medical University Guangzhou, 510315, China
3. Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA
*These authors contributed equally to this work

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Citation:
Zhang W, Song Z, Xiao J, Liu X, Luo Y, Yang Z, Luo R, Li A. Blocking the PD-1/PD-L1 axis in dendritic cell-stimulated Cytokine-Induced Killer Cells with pembrolizumab enhances their therapeutic effects against hepatocellular carcinoma. J Cancer 2019; 10(11):2578-2587. doi:10.7150/jca.26961. Available from http://www.jcancer.org/v10p2578.htm

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Abstract

Immune checkpoint therapies for cancer, like the anti-programmed cell death 1 (PD-1) agent pembrolizumab, have gained considerable attention. However, the use of immune checkpoint inhibitors in the context of adoptive immunotherapy is poorly characterized. We investigated the therapeutic efficacy of dendritic cell-stimulated CIK (DC-CIK) cells pretreated with pembrolizumab against hepatocellular carcinoma (HCC) in cytotoxicity assay in vitro and in a nude mouse xenograft model. We used time-lapse imaging to investigate tumor killing. We also performed a survival analysis based on lymphocyte subpopulation-specific mRNA signatures using The Cancer Genome Atlas (TCGA) HCC cohort (n=371 patients). The results indicated that PD-1 inhibition increased the anti-tumor effects of DC-CIK cells over those of DC-CIK cells alone, resulting in a survival benefit importantly. Time-lapse imaging revealed that DC-CIK cells appeared to be more effective and aggressive after anti-PD-1 treatment than after culture in control conditions. The PD-1 inhibitor also induced more effective immune cell infiltration of the tumor. Our analysis of the TCGA HCC cohort confirmed that a genetic signature consistent with a high degree of intratumoral CD8+ T cell infiltration is associated with good prognosis. These results suggest that blockade of the PD-1/PD-L1 axis in DC-CIK cells with a PD-1 inhibitor prior to infusion is a promising therapeutic strategy against HCC.

Keywords: PD-1, dendritic cells, cytokine-induced killer cells, immunotherapy, hepatocellular carcinoma