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. 2013 Jul 26;437(2):287-91.
doi: 10.1016/j.bbrc.2013.06.068. Epub 2013 Jun 27.

Cytomegalovirus-based cancer vaccines expressing TRP2 induce rejection of melanoma in mice

Guangwu Xu  1 , Tameka Smith, Finn Grey, Ann B Hill
Affiliations

Cytomegalovirus-based cancer vaccines expressing TRP2 induce rejection of melanoma in mice

Guangwu Xu et al. Biochem Biophys Res Commun. .

Abstract

Cytomegalovirus (CMV) induces strong and long-lasting immune responses, which make it an attractive candidate for a cancer vaccine vector. In this study, we tested whether a tumor antigen expressed in CMV can induce a strong anti-tumor effect. We expressed an unmodified melanoma antigen, mouse tyrosinase-related protein 2 (TRP2), in mouse cytomegalovirus (MCMV). Prophylactic vaccination of the mice with a single dose of MCMV-TRP2 induced rejection of B16 melanoma challenge; therapeutic vaccination with MCMV-TRP2 prolonged the survival of the mice challenged with B16 cells. Additionally, vaccination with MCMV-TRP2 five months before tumor challenge still induced tumor rejection, which indicated that the vaccine induced long-term protection. Furthermore, MCMV-TRP2 protected mice against B16 melanoma challenge regardless of the pre-existing CMV infection. We found that vaccination with MCMV-TRP2 induced long-lasting TRP2 specific antibodies but not CD8 T cells. In addition, depletion of CD4 and CD8 T cells did not compromise the antitumor effect by MCMV-TRP2; while in B cell deficient (μMT) mice, the vaccine lost its antitumor effect. These results indicate that antibodies, not T cells, are important in mediating the antitumor effect during the effector phase by the vaccine. We also made a spread deficient MCMV-TRP2 lacking the essential glycoprotein gL, which showed a similar antitumor effect. In conclusion, our study indicates that tumor antigen (TRP2) expressed in MCMV induces a strong and long-lasting anti-melanoma effect through an antibody-dependent mechanism. Our findings demonstrate that CMV might be a promising vector for the development of cancer vaccines.

Keywords: Cancer vaccine; Cytomegalovirus; Melanoma; Tyrosinase related protein 2.

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Conflict of interest statement

Conflict of Interest: The authors have declared that no conflict of interest exists.

Figures

Fig 1
Fig 1. MCMV-TRP2 induced potent antitumor effect
(A) Antitumor effect of MCMV-TRP2 in a prophylactic setting. Mice were vaccinated i.p with 4 × 106 pfu of MCMV- TRP2 or control vector (MCMV). Seven days later, mice were challenged with 2 × 105 B16-F10 melanoma cells by s.c. injection into the flank. (B) Antitumor effect of MCMV-TRP2 in a therapeutic setting. Mice were injected with 2 × 105 B16-F10 cells s.c. and then vaccinated with a single injection of MCMV-TRP2 or MCMV 3 days later. * p<0.05.
Fig 2
Fig 2. T cells are not required during the effector phase
(A) TRP2 specific CD8+ T cell response elicited by MCMV-TRP2. Frequency of IFNγ secreting CD8 T cells was measured by intracellular staining and expressed as percentage of total CD8+ T cells (mean value ± SEM). (B) Groups of mice were immunized with MCMV or MCMV-TRP2. Seven days later, mice were challenged with B16 tumor cells. The mice were treated with antibodies to CD4 (GK1.5), CD8 (2.43) or control antibody (rat IgG) at a dose of 300 μg every 3 days for a total of 5 times. The injection of antibodies was started 2 days before the tumor challenge. Data shown are the representative of two independent experiments.
Fig 3
Fig 3. Humoral immunity is required for the antitumor effect by MCMV-TRP2
(A) Vaccination induced TRP2 specific antibodies. TRP2 specific antibodies were measured by Western blot with cell lysate of B16 cells or 293 cells (as a negative control). A commercial TRP2 specific antibody was used as the positive control. (B) TRP2 was expressed on the cell surface of B16 melanoma cells. B16 and NIH3T3 cells were stained with sera containing antiTRP2 antibodies and analyzed by flow cytometry. (C) TRP2 specific antibodies persist at high levels after the vaccination. (D) Wt B6 mice and μMT mice were immunized with MCMV-TRP2. Seven days later, mice were challenged with B16 tumor cells. (E) Naïve B6 mice were transferred with sera from mice immunized with MCMV-TRP2. Mice were challenged with B16 tumor cells on the day when mice receiving the second sera transfer.
Fig 4
Fig 4. Spread deficient MCMV-TRP2 showed similar antitumor effect
(A) B6 mice were immunized with MCMV, MCMV-TRP2 or ΔgL-MCMV-TRP2. Seven days later, mice were challenged with B16 tumor cells. (B) Long-term protection by MCMV-TRP2. Mice received a single i.P. injection of MCMV-TRP vaccines 5 months before the subcutaneous B16 tumor challenge. (C) MCMV-TRP2 protected mice against tumor challenge regardless of pre-existing CMV infection. Mice were infected with 2×105 MCMV three months before the vaccination. They were challenged with B16 cells seven days after the vaccination. MCMV group has six mice; and both MCMV-TRP2 and ΔgL-MCMV-TRP2 groups have seven mice.
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