Cancer Gene Ther. 2013 Sep;20(9):493-8.

Enhancement of systemic tumor immunity for squamous cell carcinoma cells by an oncolytic herpes simplex virus.

Meshii N1, Takahashi G1, Okunaga S1, Hamada M1, Iwai S1, Takasu A1, Ogawa Y2, Yura Y1.

1Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan

2Department of Oral Pathology, Osaka University Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan

 

ABSTRACT

RH2 is a neurovirulent g134.5 gene-deficient herpes simplex virus type 1 (HSV-1) with a lytic ability in human squamous cell carcinoma cells (SCC); it is related to spontaneously occurring HSV-1 mutant HF10. The effect of RH2 on SCC was examined using a syngeneic C3H mouse model. After infection of mouse SCCVII cells with RH2, cell viability was decreased at first, but recovered by prolonged culture, indicating the limited replication of RH2. The antitumor ability of RH2 was examined using a bilateral SCCVII tumor model. The growth of the RH2-injected tumors was suppressed compared with that of phosphate-buffered saline (PBS)-injected tumors. Moreover, the growth of contralateral tumor of RH2-treated mice was also suppressed significantly. The splenocytes of C3H mice treated with RH2 lysed more SCCVII cells than NFSaY83 cells and YAC-1 cells. The cytotoxicity of the splenocytes on SCCVII cells was significantly greater than that of splenocytes from tumor-bearing mice. Removal of CD8+ T cells from splenocytes decreased their cell killing activity remarkably. The antitumor effect of RH2 on SCCVII xenografts in nude mice was not demonstrated. These results indicate that RH2 exhibited a suppressive effect on mouse SCC, even if the replication of RH2 was limited. This is ascribed to the ability of RH2 to enhance existing tumor-specific cytotoxic T lymphocyte activity.

PMID: 23887644

 

SUPPLEMENTARY

Oncolytic virotherapy is based on the ability of an attenuated virus to destroy infected tumor cells. In addition to their proven efficacy against a variety of tumors through a direct cytotoxic effect, these viruses can activate innate and/or adaptive tumor immunity.

RH2 used in the present study produce large syncytia in human SCC cells and xenografts in nude mouse, but the replication of RH2 was limited in mouse squamous cell carcinoma SCCVII cells. Nevertheless, RH2 significantly suppressed the growth of SCCVII tumor. Furthermore, contralateral tumors were also suppressed, although the effect was less than that on the RH2-injected tumors, indicating that limited virus replication is sufficient to promote tumor immunity in this model.

Cytotoxicity of the splenocytes for SCCVII, NF83Y cells and YAC-1 cells sensitive to NK cells was similar, showing the presence of innate immune cells. RH2 did not inhibit the growth of mouse SCCVII tumor in nude mice. Thus, it is unlikely that innate immunity plays a major role in the RH2-mediated regression of SCCVII tumors.

We found that the depletion of CD8+ T cells from splenocytes resulted in marked reduction of CTL activity on SCCVII cells. On the other hand, specific cytotoxicity to SCCVII was demonstrated in the splenocytes of untreated tumor-bearing mice. Thus, it can be stated that RH2 enhances the existing CTL activity of the splenocytes.

Yoshiaki Yura-fig1

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