STAT3-blocked whole-cell hepatoma vaccine induces cellular and humoral immune response against HCC

Abstract

BackgroundWhole-cell tumor vaccines have shown much promise; however, only limited success has been achieved for the goal of eliciting robust tumor-specific T-cell responses.MethodsHepatocellular carcinoma (HCC) cells, H22 and Hepa1–6, were modified by blocking the STAT3 signaling pathway with a STAT3 decoy oligodeoxynucleotide, and the immunogenicity and possibility of using these cell lysates as a vaccine were evaluated.ResultsSTAT3-blocked whole HCC cell lysates inhibited tumor growth and tumorigenesis, and prolonged the survival of tumor-bearing mice. In addition, STAT3-blocked whole HCC cell lysates stimulated the activation of T cells and natural killer (NK) cells, and enhanced the infiltration of cytotoxic CD8+ T cells in the tumor tissues. In addition, the maturation of dendritic cells (DCs) was enhanced, which promoted the generation of immunological memory against HCC. Furthermore, secondary immune responses could be primed as soon as these immunized mice were challenged with HCC cells, accompanied by T cell and NK cell activation and infiltration. Additionally, immunization with this vaccine decreased the generation of Tregs and the production of TGF-β and IL-10. Importantly, STAT3-blocked whole HCC cell lysates prevented HCC-mediated exhaustion of T cells and NK cells, showing low expression of checkpoint molecules such as PD-1 and TIGIT on T cells and NK cells in the immunized mice.ConclusionsThe newly generated STAT3-blocked whole-cell HCC vaccine has potential for cancer cell vaccination.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0623-0) contains supplementary material, which is available to authorized users.

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“…For instance, STAT3-blocked whole-cell hepatoma vaccine has been shown to elicit cellular and humoral immune responses against HCC. 36 Moreover, STAT3 was shown to markedly aggravate epithelial-to-mesenchymal transition and migration in HCC cells. 37 Additionally, STAT3 mediates HCC metastasis through regulating HOXD-AS1.…”

Immune checkpoint therapy in liver cancer

“…LAG-3 is another important inhibitory immune check point and exerts synergistic effects with PD-1/PD-L1 on T cell activation in the tumor microenvironment. In HCC-vaccine-immunized mice, STAT3-blocked HCC vaccine downregulated expression of PD-1, TIGIT, and LAG-3, which could prevent cancer-induced dysfunction of CD8+ T and natural killer cells [ 34 ]. Recently, expression of LAG3 was found to be significantly higher on tumor-associated antigen (TAA)-specific CD8+ tumor-infiltrating T helper cells and CD8+ cytotoxic T cells in tumors than those in tumor-free liver tissues and blood of HCC patients [ 35 ].…”

Expression levels of a gene signature in hiPSC associated with lung adenocarcinoma stem cells and its capability in eliciting specific antitumor immune‐response in a humanized mice model

“…Tumor‐associated antigen‐based vaccines provide protective immunity by inducing antigen‐specific immune responses . However, immunization with one or several antigens may fail to control tumor development.…”