ECSA/DPPA2 is an Embryo-Cancer Antigen that Is Coexpressed with Cancer-Testis Antigens in Non–Small Cell Lung Cancer

Purpose: Cancer cells recapitulate many behaviors of pluripotent embryonic cells such as unlimited proliferation, and the capacity to self-renew and to migrate. Embryo-cancer sequence A (ECSA), later named developmental pluripotency associated-2 (DPPA2), is an embryonic gene initially isolated from pluripotent human preimplantation embryos. We hypothesized that ECSA/DPPA2 would be quiescent in most normal tissues but expressed in cancers and may therefore be a useful target for immunotherapy. Experimental Design:ECSA/DPPA2 expression was examined in a panel of normal and tumor tissue by reverse transcription PCR, quantitative real-time PCR, and immunohistochemistry. A panel of 110 non–small cell lung cancers (NSCLC) were further investigated for the presence of ECSA/DPPA2 transcripts and several cancer testis antigens (CTA). Sera from 104 patients were analyzed for spontaneous ECSA/DPPA2 antibody production by ELISA and Western blot. Results:ECSA/DPPA2 transcripts were limited to normal testis, placenta, bone marrow, thymus, and kidney but expressed in a variety of tumors most notably in 30% of NSCLC. Enrichment for CTAs in ECSA/DPPA2-positive NSCLC was observed. Immunohistochemistry confirmed nuclear and cytoplasmic localization in subpopulations of cells with coexpression of the CTA MAGE-A3. Antibodies to recombinant ECSA/DPPA2 protein were detected in the sera of 4 of 104 patients with NSCLC but not in healthy controls. Conclusions: The restricted expression in normal tissues, expression in tumors with coexpression of CTAs, and spontaneous immunogenicity indicate that ECSA/DPPA2 is a promising target for antigen-specific immunotherapy in NSCLC.

[1]  J. Crowley,et al.  Frequent and specific immunity to the embryonal stem cell–associated antigen SOX2 in patients with monoclonal gammopathy , 2007, The Journal of experimental medicine.

[2]  Y. Atlasi,et al.  OCT‐4, an embryonic stem cell marker, is highly expressed in bladder cancer , 2007, International journal of cancer.

[3]  I. Weissman,et al.  Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma , 2007, Proceedings of the National Academy of Sciences.

[4]  A. Sinclair,et al.  Dppa2 and Dppa4 Are Closely Linked SAP Motif Genes Restricted to Pluripotent Cells and the Germ Line , 2007, Stem cells.

[5]  N. Mongan,et al.  The putative human stem cell marker, Rex‐1 (Zfp42): Structural classification and expression in normal human epithelial and carcinoma cell cultures , 2006, Molecular carcinogenesis.

[6]  J. Nemunaitis,et al.  Antitumor activity of an oncolytic adenovirus-delivered oncogene small interfering RNA. , 2006, Cancer research.

[7]  Radu Dobrin,et al.  Dissecting self-renewal in stem cells with RNA interference , 2006, Nature.

[8]  S. Kummar,et al.  Non-small-cell lung cancer vaccine therapy: a concise review. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  A. Hart,et al.  The pluripotency homeobox gene NANOG is expressed in human germ cell tumors , 2005, Cancer.

[10]  A. Clark,et al.  Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma , 2005, Cancer.

[11]  Lloyd J. Old,et al.  Cancer/testis antigens, gametogenesis and cancer , 2005, Nature Reviews Cancer.

[12]  Renato Martins,et al.  Erlotinib in previously treated non-small-cell lung cancer. , 2005, The New England journal of medicine.

[13]  Lesley Seymour,et al.  Erlotinib in lung cancer - molecular and clinical predictors of outcome. , 2005, The New England journal of medicine.

[14]  Christina Backes,et al.  Complex humoral immune response against a benign tumor: frequent antibody response against specific antigens as diagnostic targets. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Danila Coradini,et al.  Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. , 2005, Cancer research.

[16]  Austin G Smith,et al.  Self-renewal of teratocarcinoma and embryonic stem cells , 2004, Oncogene.

[17]  Mark Shackleton,et al.  Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  E. Hirschowitz,et al.  Autologous dendritic cell vaccines for non-small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  T. Luft,et al.  NY-ESO-1 Protein Formulated in ISCOMATRIX Adjuvant Is a Potent Anticancer Vaccine Inducing Both Humoral and CD8+ T-Cell-Mediated Immunity and Protection against NY-ESO-1+ Tumors , 2004, Clinical Cancer Research.

[20]  A. Clark,et al.  Human STELLAR, NANOG, and GDF3 Genes Are Expressed in Pluripotent Cells and Map to Chromosome 12p13, a Hotspot for Teratocarcinoma , 2004, Stem cells.

[21]  D. Page,et al.  Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei , 2003, Development.

[22]  R. Schreiber,et al.  Cancer immunoediting: from immunosurveillance to tumor escape , 2002, Nature Immunology.

[23]  C. Holding,et al.  Human embryonic genes re-expressed in cancer cells , 2001, Oncogene.

[24]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[25]  W. Reik,et al.  Epigenetic Reprogramming in Mammalian Development , 2001, Science.

[26]  R. Schreiber,et al.  IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity , 2001, Nature.

[27]  D. Jäger,et al.  Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  C. Sweeney,et al.  Chemotherapy in Non-Small Cell Lung Cancer , 2000, Investigational New Drugs.

[29]  D. Jäger,et al.  Serological identification of embryonic neural proteins as highly immunogenic tumor antigens in small cell lung cancer. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[30]  E. Koonin,et al.  SAP - a putative DNA-binding motif involved in chromosomal organization. , 2000, Trends in biochemical sciences.

[31]  J. Walter,et al.  Embryogenesis: Demethylation of the zygotic paternal genome , 2000, Nature.

[32]  P. Goss,et al.  Examination of POU homeobox gene expression in human breast cancer cells , 1999, International journal of cancer.

[33]  J. Walling.  Chemotherapy for advanced non-small-cell lung cancer. , 1994, Respiratory medicine.

[34]  S. Lehnert,et al.  Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. , 1987, Development.

[35]  M. Mckneally,et al.  Postoperative empyema improves survival in lung cancer. Documentation and analysis of a natural experiment. , 1972, The New England journal of medicine.

[36]  N. Hanna.  Erlotinib in-Previously Treated Non-Small-Cell Lung CancerShepherd FA (for the National Cancer Institute of Canada Clinical Trials Group Univ of Toronto; et al N Engl J Med 353:123-132, 2005§ , 2006 .

[37]  A. Simpson,et al.  The cancer/testis genes: review, standardization, and commentary. , 2004, Cancer immunity.

[38]  David E Morris,et al.  Chemotherapeutic management of stage IV non-small cell lung cancer. , 2003, Chest.

[39]  K. Shimokata.  [Chemotherapy in non-small cell lung cancer]. , 1997, Nihon Geka Gakkai zasshi.

[40]  Y. Wei,et al.  In situ observation of lymphocyte-tumor cell interaction in human lung carcinoma. , 1989, Immunological investigations.