Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma

Yoon Joong Kang, Wanyong Zeng, Weihua Song, Bruce Reinhold, Jaewon Choi, Vladimir Brusic, Takuto Yamashita, Aditya Munshi, Cheng Li, Stephane Minvielle, Kenneth C. Anderson, Nikhil Munshi, Ellis L. Reinherz, Tetsuro Sasada

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLA-A2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLA-DOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193. Additionally, the HLA-DOB232-240-specific CTLs, but not the HLA-DOB185-193-specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM.

Original languageEnglish
Pages (from-to)343-351
Number of pages9
JournalBritish Journal of Haematology
Volume163
Issue number3
DOIs
Publication statusPublished - Nov 2013
Externally publishedYes

Fingerprint

T-Lymphocyte Epitopes
Cytotoxic T-Lymphocytes
HLA Antigens
Multiple Myeloma
varespladib methyl
Peptides
Immunotherapy
Cell Line
Microarray Analysis

Keywords

  • Cytotoxic T lymphocyte
  • DNA microarray
  • HLA-DOβ
  • Multiple myeloma
  • T cell epitope

ASJC Scopus subject areas

  • Hematology

Cite this

Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma. / Kang, Yoon Joong; Zeng, Wanyong; Song, Weihua; Reinhold, Bruce; Choi, Jaewon; Brusic, Vladimir; Yamashita, Takuto; Munshi, Aditya; Li, Cheng; Minvielle, Stephane; Anderson, Kenneth C.; Munshi, Nikhil; Reinherz, Ellis L.; Sasada, Tetsuro.

In: British Journal of Haematology, Vol. 163, No. 3, 11.2013, p. 343-351.

Research output: Contribution to journalArticle

Kang, YJ, Zeng, W, Song, W, Reinhold, B, Choi, J, Brusic, V, Yamashita, T, Munshi, A, Li, C, Minvielle, S, Anderson, KC, Munshi, N, Reinherz, EL & Sasada, T 2013, 'Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma', British Journal of Haematology, vol. 163, no. 3, pp. 343-351. https://doi.org/10.1111/bjh.12544
Kang, Yoon Joong ; Zeng, Wanyong ; Song, Weihua ; Reinhold, Bruce ; Choi, Jaewon ; Brusic, Vladimir ; Yamashita, Takuto ; Munshi, Aditya ; Li, Cheng ; Minvielle, Stephane ; Anderson, Kenneth C. ; Munshi, Nikhil ; Reinherz, Ellis L. ; Sasada, Tetsuro. / Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma. In: British Journal of Haematology. 2013 ; Vol. 163, No. 3. pp. 343-351.
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abstract = "Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLA-A2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLA-DOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193. Additionally, the HLA-DOB232-240-specific CTLs, but not the HLA-DOB185-193-specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM.",
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AU - Reinhold, Bruce

AU - Choi, Jaewon

AU - Brusic, Vladimir

AU - Yamashita, Takuto

AU - Munshi, Aditya

AU - Li, Cheng

AU - Minvielle, Stephane

AU - Anderson, Kenneth C.

AU - Munshi, Nikhil

AU - Reinherz, Ellis L.

AU - Sasada, Tetsuro

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N2 - Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLA-A2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLA-DOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193. Additionally, the HLA-DOB232-240-specific CTLs, but not the HLA-DOB185-193-specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM.

AB - Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLA-A2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLA-DOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193. Additionally, the HLA-DOB232-240-specific CTLs, but not the HLA-DOB185-193-specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM.

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