Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes

Abstract

Novel treatment modalities are required urgently in patients with hepatocellular carcinoma (HCC). A vaccine that induces cytotoxic T lymphocytes (CTLs) is an ideal strategy for cancer, and glypican-3 (GPC3) is a potential option for HCC. Blocking the programmed death-1 (PD-1)/PD-L1 pathway is a rational strategy to overcome tumor escape and tolerance toward CTLs. In the present study, we investigated whether anti-PD-1 blocking antibodies (αPD-1 Ab) enhanced the number of vaccine-induced peptide-specific CTLs in peripheral blood mononuclear cells (PBMCs) following the administration of GPC3 peptide vaccine to both patients and in a mouse model. The inhibitory receptor PD-1 was highly expressed in ex vivo GPC3-specific CTLs isolated from the PBMCs of vaccinated HCC patients. In vitro, interferon-γ induced PD-L1 expression in liver cancer cell lines. In addition, PD-1 blockade increased the number of GPC3-specific CTLs, which degranulate against liver cancer cell lines. In vivo experiments using tumor-bearing mouse models showed that the combination therapy of peptide vaccine and αPD-1 Ab suppressed tumor growth synergistically. PD-1 blockade increased the number of peptide-specific tumor-infiltrating T cells (TILs) and decreased the expression of inhibitory receptors on TILs. This study demonstrated that PD-1/PD-L1 blockade augmented the antitumor effects of a peptide vaccine by increasing the immune response of vaccine-induced CTLs, and provided a foundation for the clinical development of a combination therapy using a GPC3 peptide vaccine and αPD-1 Ab.

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…Willimsky et al reported PD-L1 expression in HCC cells and PD-1 expression in CD8 + T cells [33]. Similarly, Sawada et al showed that PD-1 is highly expressed on the CTLs of patients vaccinated with GPC3 [34]. PD-1/PD-L1 expression in tumor was significantly correlated with HCC stage, local recurrence rate and poor prognosis [35].…”

The importance of correctly timing cancer immunotherapy

“…However, as a consequence of this influx, cells in the tumor microenvironment upregulate PD-L1 resulting in incomplete tumor cell elimination. Furthermore, analysis of PBMCs following administration of a glypcian-3 (GPC3) peptide vaccine in advanced or metastatic HCC revealed a high expression of PD-1 on peptide-specific CD8 + T-cells [84]. Similarly, immunotherapy using Listeria monocytogenes (Lm)-LLO can be improved by reduction of the Tregs and MDSCs, but as it is also associated with the upregulation of PD-L1 on immune cells, in particular macrophages, the use of antibodies blocking the PD-1:PD-L1 axis is justified [85].…”

Enhancing the Anti-Tumor Effects of Cancer Peptide Vaccine Therapy

“…Therefore we employed the combination therapy by using the peptide vaccine and PD-1 blocking antibody. We demonstrated that PD-1/PD-L1 blockade enhanced the anti-tumor effects of peptide vaccines by increasing the immune response of vaccine-induced CTLs [16].…”