Oncotarget

Research Papers:

CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer

Claudia Paret, Petra Simon, Kirsten Vormbrock, Christian Bender, Anne Kölsch, Andrea Breitkreuz, Özlem Yildiz, Tana Omokoko, Stefanie Hubich-Rau, Christoph Hartmann, Sabine Häcker, Meike Wagner, Diana Barea Roldan, Abderaouf Selmi, Özlem Türeci and Ugur Sahin _

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Oncotarget. 2015; 6:25356-25367. https://doi.org/10.18632/oncotarget.4516

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Abstract

Claudia Paret1, Petra Simon2, Kirsten Vormbrock1, Christian Bender1, Anne Kölsch1, Andrea Breitkreuz2, Özlem Yildiz2, Tana Omokoko2, Stefanie Hubich-Rau3, Christoph Hartmann1,3, Sabine Häcker1, Meike Wagner1,3, Diana Barea Roldan3, Abderaouf Selmi1, Özlem Türeci1,*, Ugur Sahin1,2,3,*

1TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University Mainz, Germany

2BioNTech Cell & Gene Therapies, An der Goldgrube 12, Mainz, Germany

3Experimental Oncology, Dpt. of Medicine III, Johannes Gutenberg-University, Mainz, Germany

*These authors have contributed equally to this work

Correspondence to:

Ugur Sahin, e-mail: [email protected]

Keywords: TNBC, CXorf61, CD8+ T cell epitope, T-cell receptor cloning, immunotherapy

Received: May 24, 2015     Accepted: July 15, 2015     Published: July 29, 2015

ABSTRACT

Triple-negative breast cancer (TNBC) is a high medical need disease with limited treatment options. CD8+ T cell-mediated immunotherapy may represent an attractive approach to address TNBC. The objectives of this study were to assess the expression of CXorf61 in TNBCs and healthy tissues and to evaluate its capability to induce T cell responses.

We show by transcriptional profiling of a broad comprehensive set of normal human tissue that CXorf61 expression is strictly restricted to testis. 53% of TNBC patients express this antigen in at least 30% of their tumor cells. In CXorf61-negative breast cancer cell lines CXorf61 expression is activated by treatment with the hypomethylating agent 5-aza-2′-deoxycytidine.

By vaccination of HLA-A*02-transgenic mice with CXorf61 encoding RNA we obtained high frequencies of CXorf61-specific T cells. Cloning and characterization of T cell receptors (TCRs) from responding T cells resulted in the identification of the two HLA-A*0201-restricted T cell epitopes CXorf6166–74 and CXorf6179–87. Furthermore, by in vitro priming of human CD8+ T cells derived from a healthy donor recognizing CXorf6166–74 we were able to induce a strong antigen-specific immune response and clone a human TCR recognizing this epitope.

In summary, our data confirms this antigen as promising target for T cell based therapies.


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