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A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets

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A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets Published OnlineFirst June 26, 2014; DOI: 10.1158/0008-5472.CAN-13-3725 Cancer Integrated Systems and Technologies Research A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets Ayumu Taguchi1, Allen D. Taylor2, Jaime Rodriguez1,Muge€ Celikta¸s¸ 3, Hui Liu1, Xiaotu Ma4, Qing Zhang2, Chee-Hong Wong2, Alice Chin2, Luc Girard5,6, Carmen Behrens7, Wan L. Lam8, Stephen Lam8, John D. Minna5,6,9, Ignacio I. Wistuba1, Adi F. Gazdar5,10, and Samir M. Hanash3 Abstract Cancer/testis (CT) antigens are potential immunotherapeutic targets in cancer. However, the expression of particular antigens is limited to a subset of tumors of a given type. Thus, there is a need to identify antigens with complementary expression patterns for effective therapeutic intervention. In this study, we searched for genes that were distinctly expressed at a higher level in lung tumor tissue and the testes compared with other nontumor tissues and identified members of the VCX/Y gene family as novel CT antigens. VCX3A, a member of the VCX/Y gene family, was expressed at the protein level in approximately 20% of lung adenocarcinomas and 35% of squamous cell carcinomas, but not expressed in normal lung tissues. Among CT antigens with concordant mRNA and protein expression levels, four CT antigens, XAGE1, VCX, IL13RA2, and SYCE1, were expressed, alone or in combination, in about 80% of lung adenocarcinoma tumors. The CT antigen VCX/Y gene family broadens the spectrum of CT antigens expressed in lung adenocarcinomas for clinical applications. Cancer Res; 74(17); 1–12. Ó2014 AACR. Introduction particular CT antigens is limited to only a subset of patients Many aberrantly expressed antigens are currently being with a particular tumor type. This is the case for members of targeted as therapeutic cancer vaccines (1, 2). Cancer/testis the MAGE family and NY-ESO-1, which are expressed in 10% – (CT) antigens are specifically expressed in immune-privi- to 50% and 10% to 30% of non smallcelllungcancers leged tissues, notably the testis and placenta, and exhibit (NSCLC), respectively (4, 5), and are currently being targeted aberrant expression in various types of cancer (3). Thus, they in clinical trials of vaccine immunotherapy (6). Moreover, are highly immunogenic, without self-tolerance, and are the effectiveness of immunotherapy targeting of MAGEA3 considered promising targets for cancer immunotherapy or NY-ESO-1 is so far limited (7, 8). fi with fewer adverse effects. However, the expression of In this study, we identi ed VCX/Y genes as novel CT anti- gens. VCX/Y genes, mostly located on the X chromosome, may have arisen from a common ancestor to known CT antigens 1Department of Translational Molecular Pathology, The University of Texas SPANX and CSAG2 (9). VCX may be involved in mRNA stability MD Anderson Cancer Center, Houston, Texas. 2Fred Hutchinson Cancer (10). The expression levels of VCX/Y mRNAs were reduced in Research Center, Seattle, Washington. 3Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, normal, immortalized lung cell lines compared with lung Texas. 4Department of Molecular and Cell Biology, Center for Systems cancer cell lines. Reactivity against the protein product of Biology, The University of Texas Southwestern Medical Center at Dallas, the VCX3A gene was observed in approximately 20% of lung Dallas, Texas. 5Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. adenocarcinoma and 35% of squamous cell carcinoma (SCC) 6Department of Pharmacology, The University of Texas Southwestern tumors using tissue microarrays, whereas no expression was Medical Center at Dallas, Dallas, Texas. 7Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer detected in normal lung tissues. We further examined the Center, Houston, Texas. 8Department of Integrative Oncology, British expression patterns of multiple CT antigens in lung adeno- Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. carcinomas. We found that one or more of four CT antigens 9Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. 10Department of Pathology, The (XAGE1, IL13RA2, SYCE1, and VCX) were expressed in about University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. 80% of lung adenocarcinoma tumors. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Materials and Methods Corresponding Author: Ayumu Taguchi, Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Cell culture and transfection 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-8069; All lung cancer cell lines used in this study were cultured in Fax: 713-563-5746; E-mail: [email protected] RPMI1640 containing 10% FBS and 1% penicillin/streptomycin doi: 10.1158/0008-5472.CAN-13-3725 cocktail (Gibco). Human bronchial epithelial cells (HBEC30- Ó2014 American Association for Cancer Research. KT) were cultured with keratinocyte serum-free medium (Life www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst June 26, 2014; DOI: 10.1158/0008-5472.CAN-13-3725 Taguchi et al. Technologies, Inc.) that contained 50 mg/mL bovine pituitary when mRNA expression levels were < 0.5-fold lower than extract (Life Technologies) and 5 ng/mL EGF (Life Techno- those in adjacent normal tissues. logies). Human small airway epithelial (HSAEC1-KT) cells were cultured with Small AirwayEpithelialCellGrowth Gene expression analysis Medium (SAGM, Lonza) according to the manufacturer's Total RNA was extracted from cell lines and tissues using protocol. For the siRNA transfection experiments, two siR- the RNeasy Plus Mini Kit (Qiagen). RNA quality and concen- NAs that targeted VCX (#1: Hs_VCX_8 FlexiTube siRNA, tration were checked using the Experion Automated Electro- cat. #SI04173568, and #2: Hs_VCX_10 FlexiTube siRNA, cat. phoresis System (Bio-Rad) according to the manufacturer's #SI04187295) were obtained from Qiagen. PC-9 cells were protocol. Expression data were obtained using Illumina transfected at a final concentration of 50 nmol/L siRNA Human WG-6 v3.0 Expression BeadChips (Illumina) in the using Lipofectamine RNAiMAX (Life Technologies), accord- Genomics Core at The University of Texas Southwestern ing to the manufacturer's instructions. Seventy-two hours Medical Center at Dallas (Dallas, TX). Bead-summarized data after transfection, protein was harvested using RIPA buffer were obtained using Illumina BeadStudio software and pre- for Western blotting, and an MTS assay (CellTiter 96 Aque- processed using the R software package MBCB (Model-based ous One Solution Cell Proliferation Assay, Promega) was Background Correction for Beadarray) for background correc- performed according to the manufacturer's protocol. Three tion and probe summarization. Preprocessed data were quan- independent experiments for the MTS assay were performed tile normalized and log transformed. in triplicate. For treatment with 5-aza-20-deoxycytidine (5- Aza-dC; Sigma), cells were incubated with 2 mmol/L 5-Aza- Mass spectrometry analysis dC. Media were changed every 24 hours. After 5 days, total A mass spectrometry analysis of cell lines was performed RNA was extracted from cell lines using the RNeasy Plus as previously described (14). In brief, all cell lines were grown Mini Kit (Qiagen). in RPMI1640 (Pierce) that contained 10% of dialyzed FBS (Invitrogen), 1% penicillin and streptomycin cocktail, and Quantitative real-time reverse transcription-PCR 13C-lycine instead of regular lysine for seven passages, Complementary DNA samples were prepared using the according to the standard SILAC (stable isotope labeling High-Capacity cDNA Reverse Transcription Kit (Life Techno- by amino acids in cell culture) protocol (15). The same batch logies). A TaqMan PCR assay was performed with a 7500 Fast of cells was used to analyze the whole cell extract (WCE), Real-Time PCR System, TaqMan PCR master mix, commer- conditioned media, and cell surface proteins. WCEs, condi- VCX3A cially available primers, FAM-labeled probes for the tioned media, and cell surface proteins were fractionated by 18S gene (Hs04191277_gH), and VIC-labeled probes for reverse-phase chromatography using 2 mg, 1 mg, and 0.5 mg (Hs99999901_S1), according to the manufacturer's instruc- of total protein, respectively. Cell extracts were reduced tions (Life Technologies). Each sample was run in triplicate. and alkylated with iodoacetamidebeforechromatography. C VCX3A t values for the gene were calculated and normalized Protein digestion and identification by liquid chromatogra- C 18S DC DDC to t values for ( t). The t values were then calculated phy/tandem mass spectrometry was performed as described DC by being normalized to the t value for the control. previously (16, 17). The tandem mass spectra were searched The Cancer Genome Atlas dataset against a composite database of IPI human (v3.57) and IPI fi fi The Cancer Genome Atlas (TCGA) cancer methylomes, bovine (v3.43) proteins. A xed modi cation of 6.020129 mass units was added to lysine residues for database search- measured using Illumina Human Methylation 450 BeadChips, 13 were downloaded from the TCGA website,
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