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

Scurr, Martin J. ORCID: https://orcid.org/0000-0002-4120-0688, Greenshields-Watson, Alexander, Campbell, Emma, Somerville, Michelle, Chen, Yuan, Hulin-Curtis, Sarah L. ORCID: https://orcid.org/0000-0003-0889-964X, Burnell, Stephanie E. A., Davies, James A. ORCID: https://orcid.org/0000-0003-3569-4500, Davies, Michael M. ORCID: https://orcid.org/0000-0003-3569-4500, Hargest, Rachel ORCID: https://orcid.org/0000-0001-9830-3832, Phillips, Simon, Christian, Adam D., Ashelford, Kevin E. ORCID: https://orcid.org/0000-0003-3217-2811, Andrews, Robert, Parker, Alan L. ORCID: https://orcid.org/0000-0002-9302-1761, Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182, Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004 and Godkin, Andrew ORCID: https://orcid.org/0000-0002-1910-7567 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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Abstract

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:	Advanced Research Computing @ Cardiff (ARCCA) 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:	06 Nov 2024 06:00
URI:	https://orca.cardiff.ac.uk/id/eprint/130130

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