Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6: The combined effects of bortezomib and interferon-γ on the presentation of a cryptic epitope

Satoko Morishima, Yoshiki Akatsuka, Akihiro Nawa, Eisei Kondo, Tohru Kiyono, Hiroki Torikai, Toru Nakanishi, Yoshinori Ito, Kunio Tsujimura, Kosuke Iwata, Koji Ito, Yushihisa Kodera, Yasuo Morishima, Kiyotaka Kuzushima, Toshitada Takahashi

Research output: Contribution to journalArticle

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Abstract

About 50% of cervical cancers are associated with human papillomavirus type 16 (HPV-16), and since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E649-57 epitope restricted by HLA-A*2402, which is the most commun allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA-A*2402 and HPV-16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402, the cells became susceptible to lysis when transduced with E6-E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)-γ alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN-γ fully restored CTL-mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 was found to induce IFN-γ production by specific CTLs. Tetramer analysis further revealed that induction of E649-57-specific T cells was possible in 5 of 7 patients with HPV-16-positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E649-57 peptide. Thus, these findings together indicate that E649-57 is a candidate epitope for immunotherapy and immunological monitoring of such patients.

Original languageEnglish
Pages (from-to)594-604
Number of pages11
JournalInternational Journal of Cancer
Volume120
Issue number3
DOIs
Publication statusPublished - 01-02-2007

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HLA-A24 Antigen
T-Lymphocyte Epitopes
Human papillomavirus 16
Cytotoxic T-Lymphocytes
Interferons
Epitopes
HLA-A Antigens
Uterine Cervical Neoplasms
Immunotherapy
Immunologic Monitoring
Cell Line
Proteasome Inhibitors
Cervical Intraepithelial Neoplasia
Bortezomib
HEK293 Cells
Oncogene Proteins
Japan
Clone Cells
Alleles
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Morishima, Satoko ; Akatsuka, Yoshiki ; Nawa, Akihiro ; Kondo, Eisei ; Kiyono, Tohru ; Torikai, Hiroki ; Nakanishi, Toru ; Ito, Yoshinori ; Tsujimura, Kunio ; Iwata, Kosuke ; Ito, Koji ; Kodera, Yushihisa ; Morishima, Yasuo ; Kuzushima, Kiyotaka ; Takahashi, Toshitada. / Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6 : The combined effects of bortezomib and interferon-γ on the presentation of a cryptic epitope. In: International Journal of Cancer. 2007 ; Vol. 120, No. 3. pp. 594-604.
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abstract = "About 50{\%} of cervical cancers are associated with human papillomavirus type 16 (HPV-16), and since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E649-57 epitope restricted by HLA-A*2402, which is the most commun allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA-A*2402 and HPV-16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402, the cells became susceptible to lysis when transduced with E6-E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)-γ alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN-γ fully restored CTL-mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 was found to induce IFN-γ production by specific CTLs. Tetramer analysis further revealed that induction of E649-57-specific T cells was possible in 5 of 7 patients with HPV-16-positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E649-57 peptide. Thus, these findings together indicate that E649-57 is a candidate epitope for immunotherapy and immunological monitoring of such patients.",
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Morishima, S, Akatsuka, Y, Nawa, A, Kondo, E, Kiyono, T, Torikai, H, Nakanishi, T, Ito, Y, Tsujimura, K, Iwata, K, Ito, K, Kodera, Y, Morishima, Y, Kuzushima, K & Takahashi, T 2007, 'Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6: The combined effects of bortezomib and interferon-γ on the presentation of a cryptic epitope', International Journal of Cancer, vol. 120, no. 3, pp. 594-604. https://doi.org/10.1002/ijc.22312

Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6 : The combined effects of bortezomib and interferon-γ on the presentation of a cryptic epitope. / Morishima, Satoko; Akatsuka, Yoshiki; Nawa, Akihiro; Kondo, Eisei; Kiyono, Tohru; Torikai, Hiroki; Nakanishi, Toru; Ito, Yoshinori; Tsujimura, Kunio; Iwata, Kosuke; Ito, Koji; Kodera, Yushihisa; Morishima, Yasuo; Kuzushima, Kiyotaka; Takahashi, Toshitada.

In: International Journal of Cancer, Vol. 120, No. 3, 01.02.2007, p. 594-604.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6

T2 - The combined effects of bortezomib and interferon-γ on the presentation of a cryptic epitope

AU - Morishima, Satoko

AU - Akatsuka, Yoshiki

AU - Nawa, Akihiro

AU - Kondo, Eisei

AU - Kiyono, Tohru

AU - Torikai, Hiroki

AU - Nakanishi, Toru

AU - Ito, Yoshinori

AU - Tsujimura, Kunio

AU - Iwata, Kosuke

AU - Ito, Koji

AU - Kodera, Yushihisa

AU - Morishima, Yasuo

AU - Kuzushima, Kiyotaka

AU - Takahashi, Toshitada

PY - 2007/2/1

Y1 - 2007/2/1

N2 - About 50% of cervical cancers are associated with human papillomavirus type 16 (HPV-16), and since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E649-57 epitope restricted by HLA-A*2402, which is the most commun allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA-A*2402 and HPV-16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402, the cells became susceptible to lysis when transduced with E6-E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)-γ alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN-γ fully restored CTL-mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 was found to induce IFN-γ production by specific CTLs. Tetramer analysis further revealed that induction of E649-57-specific T cells was possible in 5 of 7 patients with HPV-16-positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E649-57 peptide. Thus, these findings together indicate that E649-57 is a candidate epitope for immunotherapy and immunological monitoring of such patients.

AB - About 50% of cervical cancers are associated with human papillomavirus type 16 (HPV-16), and since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E649-57 epitope restricted by HLA-A*2402, which is the most commun allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA-A*2402 and HPV-16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402, the cells became susceptible to lysis when transduced with E6-E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)-γ alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN-γ fully restored CTL-mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 was found to induce IFN-γ production by specific CTLs. Tetramer analysis further revealed that induction of E649-57-specific T cells was possible in 5 of 7 patients with HPV-16-positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E649-57 peptide. Thus, these findings together indicate that E649-57 is a candidate epitope for immunotherapy and immunological monitoring of such patients.

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