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

Scurr, Martin J. ORCID:, Greenshields-Watson, Alexander, Campbell, Emma, Somerville, Michelle, Chen, Yuan, Hulin-Curtis, Sarah L. ORCID:, Burnell, Stephanie E. A., Davies, James A. ORCID:, Davies, Michael M. ORCID:, Hargest, Rachel ORCID:, Phillips, Simon, Christian, Adam D., Ashelford, Kevin E. ORCID:, Andrews, Robert, Parker, Alan L. ORCID:, Stanton, Richard J. ORCID:, Gallimore, Awen ORCID: and Godkin, Andrew ORCID: 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: 14 Jun 2024 17:00

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