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Broadly expressed, highly differentiated tumor-associated antigens (TAA) can elicit antitumor immunity. However, vaccines targeting TAAs have demonstrated disappointing clinical results, reflecting poor antigen selection and/or immunosuppressive mechanisms. Here, a panel of widely expressed, novel colorectal TAAs were identified by performing RNA sequencing of highly purified colorectal tumor cells in comparison with patient-matched colonic epithelial cells; tumor cell purification was essential to reveal these genes. Candidate TAA protein expression was confirmed by IHC, and preexisting T-cell immunogenicity toward these antigens tested. 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 IFNγ+ response was markedly magnified by control of immunosuppression with cyclophosphamide in patients with cancer. 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. ©2020 American Association for Cancer Research.

Citation

Martin J Scurr, Alex Greenshields-Watson, Emma Campbell, Michelle S Somerville, Yuan Chen, Sarah L Hulin-Curtis, Stephanie E A Burnell, James A Davies, Michael M Davies, Rachel Hargest, Simon Phillips, Adam D Christian, Kevin E Ashelford, Robert Andrews, Alan L Parker, Richard J Stanton, Awen Gallimore, Andrew Godkin. Cancer Antigen Discovery Is Enabled by RNA Sequencing of Highly Purified Malignant and Nonmalignant Cells. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Jul 01;26(13):3360-3370


PMID: 32122920

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