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Cancer antigen discovery is enabled by RNA-sequencing of highly purified malignant and non-malignant cells

Scurr, Martin J., Greenshields-Watson, Alexander, Campbell, Emma, Somerville, Michelle, Chen, Yuan, Hulin-Curtis, Sarah L., Burnell, Stephanie E. A., Davies, James A., Davies, Michael M., Hargest, Rachel, Phillips, Simon, Christian, Adam D., Ashelford, Kevin E., Andrews, Robert, Parker, Alan L., Stanton, Richard J., Gallimore, Awen and Godkin, Andrew 2020. Cancer antigen discovery is enabled by RNA-sequencing of highly purified malignant and non-malignant cells. Clinical Cancer Research 10.1158/1078-0432.CCR-19-3087

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Purpose: Broadly expressed, highly differentiated tumor-associated antigens (TAA) can elicit anti-tumor immunity. However, vaccines targeting TAAs have demonstrated disappointing clinical results, reflecting poor antigen selection and/or immunosuppressive mechanisms. Experimental design: Here, a panel of widely expressed, novel colorectal TAAs were identified by performing RNA sequencing of highly purified colorectal tumor cells in comparison to patient-matched colonic epithelial cells; tumor cell purification was essential to reveal these genes. Candidate TAA protein expression was confirmed by immunohistochemistry, and pre-existing T cell immunogenicity towards these antigens tested. Results: The most promising candidate for further development is DNAJB7 [DnaJ heat shock protein family (Hsp40) member B7], identified here as a novel cancer-testis antigen. It is expressed in many tumors and is strongly immunogenic in patients with cancers originating from a variety of sites. DNAJB7-specific T cells were capable of killing colorectal tumor lines in vitro, and the IFN-gamma+ response was markedly magnified by control of immunosuppression with cyclophosphamide in cancer patients. Conclusion: This study highlights how prior methods that sequence whole tumor fractions (i.e. inclusive of alive/dead stromal cells) for antigen identification may have limitations. Through tumor cell purification and sequencing, novel candidate TAAs have been identified for future immunotherapeutic targeting.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Wales Cancer Research Centre (WCRC)
Publisher: American Association for Cancer Research
ISSN: 1078-0432
Funders: Cancer Research Wales, Wellcome Trust, Cancer Research UK, Wales Cancer Research Centre
Date of First Compliant Deposit: 11 March 2020
Date of Acceptance: 26 February 2020
Last Modified: 02 Mar 2021 03:05

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