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

Paret, C., Simon, P., Vormbrock, K., Bender, C., Kölsch, A., Breitkreuz, A., Yildiz, Ö., Omokoko, T., Hubich-Rau, S., Hartmann, C., Häcker, S., Wagner, M., Roldan, D.B., Selmi, A., Türeci, Ö., Sahin, U.

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. 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. 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.

Citation

Paret, C., Simon, P., Vormbrock, K., Bender, C., Kölsch, A., Breitkreuz, A., Yildiz, Ö., Omokoko, T., Hubich-Rau, S., Hartmann, C., Häcker, S., Wagner, M., Roldan, D.B., Selmi, A., Türeci, Ö., Sahin, U. "CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer" Oncotarget (2015): 25,356–67