A search for novel cancer/testis antigens in lung cancer identifies VCX/Y genes, expanding the repertoire of potential immunotherapeutic targets - PubMed (original) (raw)

. 2014 Sep 1;74(17):4694-705.

doi: 10.1158/0008-5472.CAN-13-3725. Epub 2014 Jun 26.

Allen D Taylor 2, Jaime Rodriguez 3, Müge Celiktaş 4, Hui Liu 3, Xiaotu Ma 5, Qing Zhang 2, Chee-Hong Wong 2, Alice Chin 2, Luc Girard 6, Carmen Behrens 7, Wan L Lam 8, Stephen Lam 8, John D Minna 9, Ignacio I Wistuba 3, Adi F Gazdar 10, Samir M Hanash 4

Affiliations

A search for novel cancer/testis antigens in lung cancer identifies VCX/Y genes, expanding the repertoire of potential immunotherapeutic targets

Ayumu Taguchi et al. Cancer Res. 2014.

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.

©2014 American Association for Cancer Research.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Identification of VCX/Y genes as novel CT antigens in lung cancer.

A. Workflow for selecting novel CT antigen candidates in BioGPS. B. Heatmap for gene expression levels of VCX/Y family genes in 148 lung cancer and 59 normal lung immortalized cell lines: adenocarcinoma (n = 78), adenosquamous cell carcinoma (adenosquamous) (n = 3), SCC (n = 10), large cell carcinoma (n = 12), other NSCLC (n = 10), SCLC (n = 29), carcinoid (n = 2), mesothelioma (n = 4), bronchial epithelial (n = 30), and small airway epithelial (n = 29).

Figure 2

Figure 2. Regulatory mechanism and functional relevance of VCX/Y in NSCLC

A. Methylation levels of representative CpG sites for VCX/Y genes. P values were calculated using the Mann-Whitney U test. N, non-tumor tissue; T, tumor tissue. B. Correlation of methylation levels and mRNA expression levels in tumor tissue. C. Induction of VCX3A mRNA with 5-Aza-dC treatment in eight NSCLC cell lines. D. Western blot analysis of VCX3A protein in PC-9 and normal immortalized lung cell lines. β-tubulin was served as a loading control. E. Knockdown of VCX with siRNA in PC-9 cells was verified by Western blotting. β-tubulin was served as a loading control. F. MTS assay of PC-9 cells treated with negative control siRNA or siRNAs against VCX. Columns indicate the average of triplicate samples from a representative experiment, and bars indicate SD.

Figure 3

Figure 3. VCX3A protein expression in NSCLC tissue microarray

A. Immunohistochemical staining of VCX3A in normal lung (alveolar and bronchus) tissues. Scale bars represent 200 μm. B. Assessment of VCX3A expression levels in the nucleus of NSCLC tumor tissues. Scale bars represent 200 μm.

Figure 4

Figure 4. Transcriptomic and proteomic profiling of CT antigens in 38 NSCLC cell lines

A. Venn diagrams of CT antigens identified by mass spectrometric analysis in WCE, cell surface (surface), and conditioned media (media) of 38 NSCLC cell lines. B. CT antigens with significant correlation of expression levels between mRNA and protein. P values for comparison of mRNA expression levels in cell lines with or without CT antigen protein expression were calculated by Mann–Whitney U test. C. Schema of human VCX/Y family proteins. Black bars indicate peptides identified in the PC-9 cell line. Presented numbers are based on NP_038480.2 (VCX), NP_057462.2 (VCX2), NP_057463.2 (VCX3A), and NP_001001888.2 (VCX3B).

Figure 5

Figure 5. CT antigen panel in 83 lung adenocarcinoma patients

A. An unsupervised hierarchical clustering of 10 selected CT antigens, MAGEA3, and VCX. Black boxes in the lower heatmap indicate lung adenocarcinoma patients with CT antigen overexpression (more than two-fold higher mRNA expression levels in cases vs. controls). B. Potential epitopes of XAGE1, VCX, IL13RA2, and SYCE1. Black bars indicate 9-mer peptides with high scores in both BIMAS and SYFPEITHI. C. Receiver operating characteristic curves for autoantibodies to VCX3A in pre-diagnostic plasmas of lung and colon adenocarcinoma patients (n = 29) and matched controls (n = 29) from the WHI observational study. P values were calculated using the Mann-Whitney U test. AUC: area under the curve.

References

    1. Schlom J. Therapeutic cancer vaccines: current status and moving forward. Journal of the National Cancer Institute. 2012;104:599–613. - PMC - PubMed
    1. Dougan M, Dranoff G. Immune therapy for cancer. Annual review of immunology. 2009;27:83–117. - PubMed
    1. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nature reviews Cancer. 2005;5:615–25. - PubMed
    1. Suri A. Cancer testis antigens--their importance in immunotherapy and in the early detection of cancer. Expert Opin Biol Ther. 2006;6:379–89. - PubMed
    1. Chiriva-Internati M, Pandey A, Saba R, Kim M, Saadeh C, Lukman T, et al. Cancer testis antigens: a novel target in lung cancer. International reviews of immunology. 2012;31:321–43. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources