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

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.

Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma

“…This lack of benefit could be due to the selection of patients that could include more cases with non-immune-type HCC but also could be the result of tumor resistance to PD-1 treatment in the initial responders after repetitive cycles of treatment. Although anti-PD-1/PD-L1 therapy changes the tumor microenvironment by increasing the infiltrating CD8 T cells with cytotoxic activity [ 30 , 101 ] and can improve CD8 T cell primming by dendritic cells [ 102 ], these effects could be temporary due to the induction of compensatory inhibitory pathways [ 60 ]. Other anti-PD-1/PD-L1 monotherapies as second-line after sorafenib failure have shown also promising results, such as durvalumab (anti-PD-L1) and cemiplimab (anti-PD-1) [ 18 ].…”

Overcoming Immune Evasion in Melanoma

“…Defective antigen presentation by dendritic cells occurs as a result of the downregulation of cell surface expression of MHC II and the co-stimulatory molecules, CD80/CD86 on dendritic cells, which are essential molecules required for T cell activation [308,309]. Evidence suggest that expression of immune checkpoint molecules-CTLA-4, PD-1, PD-L1, and PD-L2 on dendritic cells, disrupts the innate immune functions and affects T-cell activation [305,[311][312][313][314][315][316]. During genetic/epigenetic changes or immune editing, melanoma subclones can successfully downregulate key components of their MHC I antigen presentation pathways, and effectively escape immune surveillance (Figure 3) [317][318][319][320][321][322][323].…”

PD-L1 in Systemic Immunity: Unraveling Its Contribution to PD-1/PD-L1 Blockade Immunotherapy

“…DCs also induce T reg expansion in a PD-L1 dependent mechanism in a murine model [ 63 ], suggesting that this immunosuppressive population might also be targeted by anti-PD-L1 immunotherapy. Moreover, the co-culture of mature DCs with cytokine-induced killer cells (CIKs, a population of CD56 + CD3 + cells with the ability to kill cancer cells in an MHC-unrestricted manner) in the presence of pembrolizumab showed an increased proliferation and cytotoxic capacity of this population in a liver cancer model in vitro and in vivo [ 64 ].…”