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Placenta-derived gp96 as a multivalent prophylactic cancer vaccine.

Zhao B, Wang Y, Wu B, Liu S, Wu E, Fan H, Gui M, Chen L, Li C, Ju Y, Zhang W, Meng S - Sci Rep (2013)

Bottom Line: A major challenge for designing prophylactic cancer vaccines is to define immunogenic and safe cancer antigens.Placental gp96 activated HER2- and MUC1-specific T cell responses through binding to tumor-associated antigens.Our results reveal the novel immunogenicity of placental gp96 and its potential use as a multivalent cancer vaccine.

View Article: PubMed Central - PubMed

Affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.

ABSTRACT
A major challenge for designing prophylactic cancer vaccines is to define immunogenic and safe cancer antigens. Given the striking similarity of antigen expression patterns between cancer and embryonic tissues, we defined a prototype strategy of using placenta-derived heat shock protein gp96, which induces prophylactic anti-tumor T cell responses. Immunization with placental gp96 provided partial protection and long-term (at least 3 months) anti-tumor immunity against growth of transplantable melanoma or breast tumors in mice, elicited total protection against 7, 12-dimethylbenz(a)-anthracene (DMBA)-induced mammary tumors in rats, and significantly reduced the occurrence and growth of autochthonous breast tumors in HER2 transgenic mice. Placental gp96 activated HER2- and MUC1-specific T cell responses through binding to tumor-associated antigens. Our results reveal the novel immunogenicity of placental gp96 and its potential use as a multivalent cancer vaccine.

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P-gp96 vaccination induces long-term protective immunity against tumors.Female C57BL/6 (a–d) or BALB/c (e–h) mice were immunized three times with P-gp96, L-gp96, or PBS. Three months after the third immunization, the mice were subcutaneously challenged with 5×104 B16-F10 cells or 6×105 TUBO cells. (a, e) Tumor burden was measured at 2-day intervals. (b, f) Kaplan-Meier plot of mouse survival after the various vaccinations. (c, g) Splenocytes from immunized mice were stimulated with B16-F10 (c) or TUBO (g) whole cell lysates antigens or BSA for background evaluation and assayed by IFN-γ ELISPOT. (d, h) Splenocytes were stimulated with irradiated B16-F10 (d) or TUBO (h) cells in vitro for 3 days and analyzed for cytotoxic activity by FACS using CFSE-labeled B16-F10 cells or TUBO cells as target cells. Error bars indicate s.d. ** P < 0.01, *** P < 0.001 (Analysis of variance (ANOVA) and post-hoc comparison using Tukey's test).
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f2: P-gp96 vaccination induces long-term protective immunity against tumors.Female C57BL/6 (a–d) or BALB/c (e–h) mice were immunized three times with P-gp96, L-gp96, or PBS. Three months after the third immunization, the mice were subcutaneously challenged with 5×104 B16-F10 cells or 6×105 TUBO cells. (a, e) Tumor burden was measured at 2-day intervals. (b, f) Kaplan-Meier plot of mouse survival after the various vaccinations. (c, g) Splenocytes from immunized mice were stimulated with B16-F10 (c) or TUBO (g) whole cell lysates antigens or BSA for background evaluation and assayed by IFN-γ ELISPOT. (d, h) Splenocytes were stimulated with irradiated B16-F10 (d) or TUBO (h) cells in vitro for 3 days and analyzed for cytotoxic activity by FACS using CFSE-labeled B16-F10 cells or TUBO cells as target cells. Error bars indicate s.d. ** P < 0.01, *** P < 0.001 (Analysis of variance (ANOVA) and post-hoc comparison using Tukey's test).

Mentions: Next, we tested whether P-gp96 immunization could provide long-term protective anti-tumor immunity. C57BL/6 mice were vaccinated three times with P-gp96 or L-gp96 derived from C57BL/6 mice. At three months after the last immunization, mice were subcutaneously inoculated with B16-F10 (5×104 cells/mouse). Compared to no treatment, tumor growth was slowed in mice treated with P-gp96 but not L-gp96 (P < 0.01) (Fig. 2a), and the survival of tumor burdened mice was also significantly enhanced (P < 0.001) (Fig. 2b). P-gp96-immunized mice exhibited a significant increase in B16-specific T cells by approximately 1.5- or 2.5-fold (Fig. 2c) and enhanced cytotoxicity of CTLs compared to L-gp96- or PBS-immunized mice (Fig. 2d). Similar results were observed in the TUBO model of P-gp96-mediated tumor growth inhibition (Fig. 2e), i.e., increased survival (Fig. 2f), a tumor-specific T cell response (Fig. 2g), and an increase in cytotoxicity (Fig. 2h). Together, these results indicate placenta-derived gp96 induced long-term T cell responses against transplanted tumors.


Placenta-derived gp96 as a multivalent prophylactic cancer vaccine.

Zhao B, Wang Y, Wu B, Liu S, Wu E, Fan H, Gui M, Chen L, Li C, Ju Y, Zhang W, Meng S - Sci Rep (2013)

P-gp96 vaccination induces long-term protective immunity against tumors.Female C57BL/6 (a–d) or BALB/c (e–h) mice were immunized three times with P-gp96, L-gp96, or PBS. Three months after the third immunization, the mice were subcutaneously challenged with 5×104 B16-F10 cells or 6×105 TUBO cells. (a, e) Tumor burden was measured at 2-day intervals. (b, f) Kaplan-Meier plot of mouse survival after the various vaccinations. (c, g) Splenocytes from immunized mice were stimulated with B16-F10 (c) or TUBO (g) whole cell lysates antigens or BSA for background evaluation and assayed by IFN-γ ELISPOT. (d, h) Splenocytes were stimulated with irradiated B16-F10 (d) or TUBO (h) cells in vitro for 3 days and analyzed for cytotoxic activity by FACS using CFSE-labeled B16-F10 cells or TUBO cells as target cells. Error bars indicate s.d. ** P < 0.01, *** P < 0.001 (Analysis of variance (ANOVA) and post-hoc comparison using Tukey's test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674428&req=5

f2: P-gp96 vaccination induces long-term protective immunity against tumors.Female C57BL/6 (a–d) or BALB/c (e–h) mice were immunized three times with P-gp96, L-gp96, or PBS. Three months after the third immunization, the mice were subcutaneously challenged with 5×104 B16-F10 cells or 6×105 TUBO cells. (a, e) Tumor burden was measured at 2-day intervals. (b, f) Kaplan-Meier plot of mouse survival after the various vaccinations. (c, g) Splenocytes from immunized mice were stimulated with B16-F10 (c) or TUBO (g) whole cell lysates antigens or BSA for background evaluation and assayed by IFN-γ ELISPOT. (d, h) Splenocytes were stimulated with irradiated B16-F10 (d) or TUBO (h) cells in vitro for 3 days and analyzed for cytotoxic activity by FACS using CFSE-labeled B16-F10 cells or TUBO cells as target cells. Error bars indicate s.d. ** P < 0.01, *** P < 0.001 (Analysis of variance (ANOVA) and post-hoc comparison using Tukey's test).
Mentions: Next, we tested whether P-gp96 immunization could provide long-term protective anti-tumor immunity. C57BL/6 mice were vaccinated three times with P-gp96 or L-gp96 derived from C57BL/6 mice. At three months after the last immunization, mice were subcutaneously inoculated with B16-F10 (5×104 cells/mouse). Compared to no treatment, tumor growth was slowed in mice treated with P-gp96 but not L-gp96 (P < 0.01) (Fig. 2a), and the survival of tumor burdened mice was also significantly enhanced (P < 0.001) (Fig. 2b). P-gp96-immunized mice exhibited a significant increase in B16-specific T cells by approximately 1.5- or 2.5-fold (Fig. 2c) and enhanced cytotoxicity of CTLs compared to L-gp96- or PBS-immunized mice (Fig. 2d). Similar results were observed in the TUBO model of P-gp96-mediated tumor growth inhibition (Fig. 2e), i.e., increased survival (Fig. 2f), a tumor-specific T cell response (Fig. 2g), and an increase in cytotoxicity (Fig. 2h). Together, these results indicate placenta-derived gp96 induced long-term T cell responses against transplanted tumors.

Bottom Line: A major challenge for designing prophylactic cancer vaccines is to define immunogenic and safe cancer antigens.Placental gp96 activated HER2- and MUC1-specific T cell responses through binding to tumor-associated antigens.Our results reveal the novel immunogenicity of placental gp96 and its potential use as a multivalent cancer vaccine.

View Article: PubMed Central - PubMed

Affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.

ABSTRACT
A major challenge for designing prophylactic cancer vaccines is to define immunogenic and safe cancer antigens. Given the striking similarity of antigen expression patterns between cancer and embryonic tissues, we defined a prototype strategy of using placenta-derived heat shock protein gp96, which induces prophylactic anti-tumor T cell responses. Immunization with placental gp96 provided partial protection and long-term (at least 3 months) anti-tumor immunity against growth of transplantable melanoma or breast tumors in mice, elicited total protection against 7, 12-dimethylbenz(a)-anthracene (DMBA)-induced mammary tumors in rats, and significantly reduced the occurrence and growth of autochthonous breast tumors in HER2 transgenic mice. Placental gp96 activated HER2- and MUC1-specific T cell responses through binding to tumor-associated antigens. Our results reveal the novel immunogenicity of placental gp96 and its potential use as a multivalent cancer vaccine.

Show MeSH
Related in: MedlinePlus