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Cancer Antigen Discovery Is Enabled by RNA Sequencing of Highly Purified Malignant and Nonmalignant Cells

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Cancer Antigen Discovery Is Enabled by RNA Sequencing of Highly Purified Malignant and Nonmalignant Cells Published OnlineFirst March 2, 2020; DOI: 10.1158/1078-0432.CCR-19-3087 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Cancer Antigen Discovery Is Enabled by RNA Sequencing of Highly Purified Malignant and Nonmalignant Cells A C Martin J. Scurr1, Alex Greenshields-Watson1, Emma Campbell1, Michelle S. Somerville1, Yuan Chen1, Sarah L. Hulin-Curtis1, Stephanie E.A. Burnell1, James A. Davies2, Michael M. Davies3, Rachel Hargest3, Simon Phillips3, Adam D. Christian4, Kevin E. Ashelford2, Robert Andrews1, Alan L. Parker2, Richard J. Stanton1, Awen Gallimore1, and Andrew Godkin1,5 ABSTRACT ◥ Purpose: Broadly expressed, highly differentiated tumor- Results: The most promising candidate for further development associated antigens (TAA) can elicit antitumor immunity. However, is DNAJB7 [DnaJ heat shock protein family (Hsp40) member B7], vaccines targeting TAAs have demonstrated disappointing clinical identified here as a novel cancer-testis antigen. It is expressed in results, reflecting poor antigen selection and/or immunosuppressive many tumors and is strongly immunogenic in patients with cancers mechanisms. originating from a variety of sites. DNAJB7-specificTcellswere þ Experimental Design: Here, a panel of widely expressed, capable of killing colorectal tumor lines in vitro,andtheIFNg novel colorectal TAAs were identified by performing RNA response was markedly magnified by control of immunosuppression sequencing of highly purified colorectal tumor cells in with cyclophosphamide in patients with cancer. comparison with patient-matched colonic epithelial cells; Conclusions: This study highlights how prior methods that tumor cell purification was essential to reveal these genes. sequence whole tumor fractions (i.e., inclusive of alive/dead stromal Candidate TAA protein expression was confirmed by IHC, cells) for antigen identification may have limitations. Through and preexisting T-cell immunogenicity toward these antigens tumor cell purification and sequencing, novel candidate TAAs have tested. been identified for future immunotherapeutic targeting. Introduction Many upregulated tumor-associated antigen (TAA) targets are often readily detectable in healthy tissue, e.g., the autoantigen carci- Despite understandable excitement surrounding results from can- noembryonic antigen (CEA), and directing immune responses against cer immunotherapy studies, actual outcomes are disappointing. We such antigens can lead to side effects (2) and poor survival outcomes recently demonstrated the principle that immunologic responses after surgery (3). Thus, identification of TAAs that can be targeted by generated to the 5T4 oncofetal antigen through MVA-5T4 (TroVax) immunotherapy is a balance between expression on tumor and healthy vaccination can positively influence the outcome of patients with tissue. The challenge is further complicated by T-cell cross-reactivity advanced colorectal cancer (1). Although survival was significantly which can result in off-target effects in distant tissue with potentially prolonged for vaccinated patients mounting an anti-5T4 response, all fatal consequences (4). patients had progressed within 10 months. Indeed, stand-alone anti- Although immunotherapies targeting neoepitopes hold promise, cancer vaccines are rarely effective in the advanced disease setting; this they are highly focused to the individual and currently prohibitively could be the result of inherent mechanisms of local immunosuppres- expensive to develop. For therapies relevant to the wider population sion, or suboptimal antigenic targets. such as cancer vaccines, antigens must be broadly expressed in the same tumor types of multiple individuals and present at minimal levels in healthy tissue. Ideal discovery pipelines would involve large-scale analysis of TAA candidates followed by selection based on immuno- 1Division of Infection and Immunity, Henry Wellcome Building, Cardiff University, genicity and tissue-specific expression. Candidates that fit these criteria Cardiff, United Kingdom. 2Division of Cancer and Genetics, Sir Geraint Evans could be explored further with cancer vaccination and CAR-T cell 3 Building, Cardiff University, Cardiff, United Kingdom. Department of Colorectal therapy. Indeed, vaccinations targeting nonmutated tumor antigens Surgery, University Hospital of Wales, Heath Park, Cardiff, United Kingdom. are capable of inducing robust T-cell responses in patients with 4Department of Histopathology, University Hospital of Wales, Heath Park, Cardiff, United Kingdom. 5Department of Gastroenterology and Hepatology, cancer (1, 5). University Hospital of Wales, Heath Park, Cardiff, United Kingdom. The development of RNA sequencing (RNA-seq) in differential expression analysis provides an attractive methodology to initiate TAA Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). discovery pipelines. However, this technology is limited by the het- erogeneity of the tissue in question and is not extensively used in TAA M.J. Scurr, A. Greenshields-Watson, A. Gallimore, and A. Godkin contributed equally to this article. discovery. For the colon, a mixture of immune cells, epithelium, and stroma complicates expression profiles, limiting identification of Corresponding Authors: Andrew Godkin, Cardiff University, Cardiff, CF14 4XN, significantly differential expressed genes (DEG) especially when tumor United Kingdom. Phone: 02920687129; Fax: 02920687079; E-mail: fi [email protected]; and Awen Gallimore, [email protected] immune in ltrate varies highly between individuals and tumor loca- tion. Purification of epithelial and tumor cells prior to RNA-seq Clin Cancer Res 2020;XX:XX–XX analysis is a novel methodology developed to overcome tissue het- doi: 10.1158/1078-0432.CCR-19-3087 erogeneity. In this study, we used EpCAM purification of tumor and Ó2020 American Association for Cancer Research. healthy colonic epithelium at two sites to improve the resolution AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 2, 2020; DOI: 10.1158/1078-0432.CCR-19-3087 Scurr et al. samples were thawed and RNA isolated using an RNeasy Micro kit Translational Relevance (Qiagen). In order for cancer vaccination strategies to realize their poten- tial, they must elicit effective antitumor immune responses in a RNA-seq broad patient population. Tumor cell purification dramatically Library preparation and RNA-seq were carried out by VGTI-FL. improves RNA sequencing resolution to the point where novel, Purified RNA was used to make libraries using an Illumina TruSeq highly differentially expressed, immunogenic proteins become kit. Libraries were sequenced to a depth of 37–63 M read detectable. This novel methodology of tumor antigen identification pairs on an Illumina HiSeq platform. Paired end reads were could enhance future vaccine efficacy. processed on a Cardiff University pipeline. Reads were trimmed with Trimmomatic (6) and assessed for quality using FastQC (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/) using the default parameters. Reads were mapped to Ensembl human fi fi between expression pro les and thus aid identi cation of DEG. Gene genome build GRCh38.89 downloaded from the Ensembl FTP site fi lists were created based on expression pro les between all tissues and (http://www.ensembl.org/info/data/ftp/index.html/) using STAR (7). fi signi cance levels in a DESeq2 comparison analysis. These lists were Counts were assigned to transcripts using featureCounts with the analyzed, and several genes selected for further investigation. Immu- GRCh38.89 gene build GTF (8). RNA-seq data have been deposited in nogenic analysis and tissue expression of the protein products of these the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayex genes in healthy tissues were used to select the best candidate for cancer press) under accession number E-MTAB-8803. immunotherapy. Differential expression analysis Materials and Methods Aligned reads were normalized using DESeq2 in R (9). DEG fi fi fi Excision of colonic and tumor tissue were identi ed between puri ed tumor samples, puri ed near, and fi Tumor and paired background (unaffected) colon specimens puri ed far epithelium. Differential expression analysis was carri- were obtained from 3 patients undergoing anterior resection for ed out using DESeq2 between sample types for all donors in a paired primary rectal cancer at the University Hospital of Wales, Cardiff analysis. Comparisons of tumor and near or far normal epithelial (see Supplementary Table S1 for patient characteristics). Autolo- tissue were carried out. For the three-donor expression analysis, gous colon samples were cut from macroscopically normal sections genes with a log 2-fold change greater than 3.5, FPKM (fragments of the excised tissue, both “near” (within 2 cm) and “far” (at least 10 per kilobase of transcript per million reads mapped) values in cm) from the tumor site. All fresh tumor samples were derived from healthy tissue less than 3.5, and FPKM values in tumor greater P the luminal aspect of the specimen, so as not to interfere with than 4.0 in any two of three donors and adjusted <0.05 [Benjamini histopathologic staging. All patients and participants gave written, and Hochberg (10), in three donors] were taken forward for informed consent personally priortoinclusion.Thisstudywas further analysis. fi conducted in accordance with the
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