Abstract
We have previously demonstrated that malaria parasite infection has an anti-tumor effect in a mouse model. This research aimed to investigate the possibility of using Plasmodium parasite as a novel vaccine vector for hepatocellular carcinoma (HCC) immunotherapy. We constructed a Plasmodium yoelii 17XNL strain (P.y) expressing murine glypican-3 (GPC3) protein (P.y-GPC3), and examined its therapeutic potency in a murine Hepa1-6-induced hepatoma model that highly expressed GPC3 protein. The prerequisites for invoking a CD8+ T cell response were assessed after P.y-based immunization, which included obviously increased concentrations of T helper cell type 1 (Th1)-associated cytokines, such as IL-2, IFN-γ and TNF-α, in serum and preferential expansion of the CD8α+ dendritic cell (DC) subset with higher expression of CD80 and CD86 molecules. Compared with uninfected and wild-type P.y-infected mice, a significant GPC3-specific cytotoxic T lymphocyte (CTL) response was detected in P.y-GPC3 vaccinated mice. Furthermore, P.y-GPC3-based vaccination dramatically inhibited Hepa1-6-induced tumor growth in the implanted HCC and prolonged the survival of tumor-bearing mice. We concluded that a Plasmodium-based vector is highly efficient in inducing tumor antigen-specific T cell-mediated immunity and protection against tumor cells. More broadly, this strategy supported our hypothesis that Plasmodium parasites, as novel therapeutic antigen vectors, may be applicable to tumor immunotherapy for patients with HCC.
Highlights
Hepatocellular carcinoma (HCC), which accounts for 85–90% of primary liver cancers, is the third most common causes of cancer mortality worldwide [1, 2]
In a phase I/II trial of alpha fetal protein (AFP) peptide-pulsed dendritic cell (DC) or GPC3-derived peptide vaccine, a transient CD8+ T cell response was detected in patients with hepatocellular carcinoma (HCC) and overall survival (OS) was positively associated with the specific cytotoxic T lymphocyte (CTL) response [13, 14]
We propose that the Plasmodium parasite could be an HCC vaccine vector for more rationales: (i) foreign protein can be expressed in parasites over a long period of infection. (ii) certain critical immunostimulatory characteristics of the parasites can enhance CTL-mediated anti-tumor immunity and prolong immune responses, and (iii) Plasmodium parasites are potent triggers of antigenspecific cytotoxic activity in CD8+ T cells
Summary
Hepatocellular carcinoma (HCC), which accounts for 85–90% of primary liver cancers, is the third most common causes of cancer mortality worldwide [1, 2]. Immunotherapy has recently become a refined strategy for tumor treatment [6,7,8,9,10], and a tumor vaccine is an important option for patients with HCC [11, 12]. In a phase I/II trial of alpha fetal protein (AFP) peptide-pulsed DCs or GPC3-derived peptide vaccine, a transient CD8+ T cell response was detected in patients with HCC and overall survival (OS) was positively associated with the specific cytotoxic T lymphocyte (CTL) response [13, 14]. An appropriate delivery vector may solve the problems of antigen retention and release in vivo and generate robust and longlasting forms of immune responses, in specific CTLs, which are critical for immunological control of HCC [12]
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