Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells

U. Thiel; S. Pirson; C. Müller-Spahn; H. Conrad; D. H. Busch; H. Bernhard; S. Burdach; G. H.S. Richter

doi:10.1038/bjc.2011.54

Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells

U. Thiel, S. Pirson, C. Müller-Spahn, H. Conrad, D. H. Busch, H. Bernhard, S. Burdach, G. H.S. Richter

Chair of Medical Microbiology, Immunology and Hygiene

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Background:The development of a successful immunotherapy is hampered by an ineffective T-cell repertoire against tumour antigens and the inability of the patient's immune system to overcome tolerance-inducing mechanisms. Here, we test the specific recognition and lytical potential of allo-restricted CD8 ⁺ T cells against Ewing tumour (ET) associated antigens Enhancer of Zeste, Drosophila Homolog 2 (EZH2), and Chondromodulin-I (CHM1) identified through previous microarray analysis.Methods:Following repetitive CHM1 ³¹⁹ (VIMPCSWWV) and EZH2 ⁶⁶⁶ (YMCSFLFNL) peptide-driven stimulations with HLA-A 0201 dendritic cells (DC), allo-restricted HLA-A 0201 CD8 ⁺T cells were stained with HLA-A 0201/peptide multimers, sorted and expanded by limiting dilution.Results:Expanded T cells specifically recognised peptide-pulsed target cells or antigen-transfected cells in the context of HLA-A 0201 and killed HLA-A 0201 ET lines expressing the antigen while HLA-A 0201- ET lines were not affected. Furthermore, adoptively transferred T cells caused significant ET growth delay in Rag2 / γ C / mice. Within this context, we identified the CHM1 ³¹⁹ peptide as a new candidate target antigen for ET immunotherapy.Conclusion:These results clearly identify the ET-derived antigens, EZH2 ⁶⁶⁶ and CHM1 ³¹⁹, as suitable targets for protective allo-restricted human CD8 T-cell responses against non-immunogenic ET and may benefit new therapeutic strategies in ET patients treated with allogeneic stem cell transplantation.

Original language	English
Pages (from-to)	948-956
Number of pages	9
Journal	British Journal of Cancer
Volume	104
Issue number	6
DOIs	https://doi.org/10.1038/bjc.2011.54
State	Published - 15 Mar 2011

Keywords

Ewing tumour
adoptive transfer
immunotherapy
multimer technology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/bjc.2011.54

Cite this

@article{989697cd6c314fc1b29bbdeb51410bfa,

title = "Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells",

abstract = "Background:The development of a successful immunotherapy is hampered by an ineffective T-cell repertoire against tumour antigens and the inability of the patient's immune system to overcome tolerance-inducing mechanisms. Here, we test the specific recognition and lytical potential of allo-restricted CD8 + T cells against Ewing tumour (ET) associated antigens Enhancer of Zeste, Drosophila Homolog 2 (EZH2), and Chondromodulin-I (CHM1) identified through previous microarray analysis.Methods:Following repetitive CHM1 319 (VIMPCSWWV) and EZH2 666 (YMCSFLFNL) peptide-driven stimulations with HLA-A 0201 dendritic cells (DC), allo-restricted HLA-A 0201 CD8 +T cells were stained with HLA-A 0201/peptide multimers, sorted and expanded by limiting dilution.Results:Expanded T cells specifically recognised peptide-pulsed target cells or antigen-transfected cells in the context of HLA-A 0201 and killed HLA-A 0201 ET lines expressing the antigen while HLA-A 0201- ET lines were not affected. Furthermore, adoptively transferred T cells caused significant ET growth delay in Rag2 / γ C / mice. Within this context, we identified the CHM1 319 peptide as a new candidate target antigen for ET immunotherapy.Conclusion:These results clearly identify the ET-derived antigens, EZH2 666 and CHM1 319, as suitable targets for protective allo-restricted human CD8 T-cell responses against non-immunogenic ET and may benefit new therapeutic strategies in ET patients treated with allogeneic stem cell transplantation.",

keywords = "Ewing tumour, adoptive transfer, immunotherapy, multimer technology",

author = "U. Thiel and S. Pirson and C. M{\"u}ller-Spahn and H. Conrad and Busch, {D. H.} and H. Bernhard and S. Burdach and Richter, {G. H.S.}",

note = "Funding Information: We thank Colette Zobywalski, Katleen G{\"o}tsch and Lynette Henkel for expert technical assistance. Petra Wolf is acknowledged for statistical advice and Thomas Gr{\"u}newald for critical reading of the manuscript and for helpful discussions. This work was supported by unrestricted special grants from the Else-Kr{\"o}ner-Fresenius Stiftung (P31/08//A123/07) and the Deutsche Kinderkrebsstiftung (DKS 2010.07) to GHSR and SB; the Bayerisches Staatsministerium f{\"u}r Wissenschaft und Kunst (KKF8739175), the Wilhelm-Sander Stiftung (2006.109.1) to SB, and (2009.901.1) to GHSR and SB and the Helmholtz Alliance Immunotherapy of Cancer and the Deutsche Forschungsgemeinschaft (1579/4-1) to HB It is part of the Translational Sarcoma Research Network supported by the Bun-desministerium f{\"u}r Bildung und Forschung (BMBF, FK 01GM0870 to GHSR and SB). ELISpot reader was kindly sponsored by the Rotary Club M{\"u}nchen-Blutenburg. UT and SP equally contributed to this work that contains part of the doctoral thesis of SP.",

year = "2011",

month = mar,

day = "15",

doi = "10.1038/bjc.2011.54",

language = "English",

volume = "104",

pages = "948--956",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "6",

}

TY - JOUR

T1 - Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells

AU - Thiel, U.

AU - Pirson, S.

AU - Müller-Spahn, C.

AU - Conrad, H.

AU - Busch, D. H.

AU - Bernhard, H.

AU - Burdach, S.

AU - Richter, G. H.S.

N1 - Funding Information: We thank Colette Zobywalski, Katleen Götsch and Lynette Henkel for expert technical assistance. Petra Wolf is acknowledged for statistical advice and Thomas Grünewald for critical reading of the manuscript and for helpful discussions. This work was supported by unrestricted special grants from the Else-Kröner-Fresenius Stiftung (P31/08//A123/07) and the Deutsche Kinderkrebsstiftung (DKS 2010.07) to GHSR and SB; the Bayerisches Staatsministerium für Wissenschaft und Kunst (KKF8739175), the Wilhelm-Sander Stiftung (2006.109.1) to SB, and (2009.901.1) to GHSR and SB and the Helmholtz Alliance Immunotherapy of Cancer and the Deutsche Forschungsgemeinschaft (1579/4-1) to HB It is part of the Translational Sarcoma Research Network supported by the Bun-desministerium für Bildung und Forschung (BMBF, FK 01GM0870 to GHSR and SB). ELISpot reader was kindly sponsored by the Rotary Club München-Blutenburg. UT and SP equally contributed to this work that contains part of the doctoral thesis of SP.

PY - 2011/3/15

Y1 - 2011/3/15

N2 - Background:The development of a successful immunotherapy is hampered by an ineffective T-cell repertoire against tumour antigens and the inability of the patient's immune system to overcome tolerance-inducing mechanisms. Here, we test the specific recognition and lytical potential of allo-restricted CD8 + T cells against Ewing tumour (ET) associated antigens Enhancer of Zeste, Drosophila Homolog 2 (EZH2), and Chondromodulin-I (CHM1) identified through previous microarray analysis.Methods:Following repetitive CHM1 319 (VIMPCSWWV) and EZH2 666 (YMCSFLFNL) peptide-driven stimulations with HLA-A 0201 dendritic cells (DC), allo-restricted HLA-A 0201 CD8 +T cells were stained with HLA-A 0201/peptide multimers, sorted and expanded by limiting dilution.Results:Expanded T cells specifically recognised peptide-pulsed target cells or antigen-transfected cells in the context of HLA-A 0201 and killed HLA-A 0201 ET lines expressing the antigen while HLA-A 0201- ET lines were not affected. Furthermore, adoptively transferred T cells caused significant ET growth delay in Rag2 / γ C / mice. Within this context, we identified the CHM1 319 peptide as a new candidate target antigen for ET immunotherapy.Conclusion:These results clearly identify the ET-derived antigens, EZH2 666 and CHM1 319, as suitable targets for protective allo-restricted human CD8 T-cell responses against non-immunogenic ET and may benefit new therapeutic strategies in ET patients treated with allogeneic stem cell transplantation.

AB - Background:The development of a successful immunotherapy is hampered by an ineffective T-cell repertoire against tumour antigens and the inability of the patient's immune system to overcome tolerance-inducing mechanisms. Here, we test the specific recognition and lytical potential of allo-restricted CD8 + T cells against Ewing tumour (ET) associated antigens Enhancer of Zeste, Drosophila Homolog 2 (EZH2), and Chondromodulin-I (CHM1) identified through previous microarray analysis.Methods:Following repetitive CHM1 319 (VIMPCSWWV) and EZH2 666 (YMCSFLFNL) peptide-driven stimulations with HLA-A 0201 dendritic cells (DC), allo-restricted HLA-A 0201 CD8 +T cells were stained with HLA-A 0201/peptide multimers, sorted and expanded by limiting dilution.Results:Expanded T cells specifically recognised peptide-pulsed target cells or antigen-transfected cells in the context of HLA-A 0201 and killed HLA-A 0201 ET lines expressing the antigen while HLA-A 0201- ET lines were not affected. Furthermore, adoptively transferred T cells caused significant ET growth delay in Rag2 / γ C / mice. Within this context, we identified the CHM1 319 peptide as a new candidate target antigen for ET immunotherapy.Conclusion:These results clearly identify the ET-derived antigens, EZH2 666 and CHM1 319, as suitable targets for protective allo-restricted human CD8 T-cell responses against non-immunogenic ET and may benefit new therapeutic strategies in ET patients treated with allogeneic stem cell transplantation.

KW - Ewing tumour

KW - adoptive transfer

KW - immunotherapy

KW - multimer technology

UR - http://www.scopus.com/inward/record.url?scp=79952681382&partnerID=8YFLogxK

U2 - 10.1038/bjc.2011.54

DO - 10.1038/bjc.2011.54

M3 - Article

C2 - 21407224

AN - SCOPUS:79952681382

SN - 0007-0920

VL - 104

SP - 948

EP - 956

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 6

ER -

Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this