NY-ESO-1 Cancer Testis Antigen Demonstrates High Immunogenicity in Triple Negative Breast Cancer

Purpose NY-ESO-1 cancer testis (CT) antigen is an attractive candidate for immunotherapy as a result of its high immunogenicity. The aim of this study was to explore the potential for NY-ESO-1 antigen directed immunotherapy in triple negative breast cancer (TNBC) by determining the frequency of expression by immunohistochemistry (IHC) and the degree of inherent immunogenicity to NY-ESO-1. Experimental Design 168 TNBC and 47 ER+/HER2- primary breast cancer specimens were used to determine NY-ESO-1 frequency by IHC. As previous studies have shown that patients with a robust innate humoral immune response to CT antigens are more likely to develop CD8 T-cell responses to NY-ESO-1 peptides, we evaluated the degree to which patients with NY-ESO-1 expression had inherent immunogenicity by measuring antibodies. The relationship between NY-ESO-1 expression and CD8+ T lymphocytes was also examined. Results The frequency of NY-ESO-1 expression in the TNBC cohort was 16% versus 2% in ER+/HER2- patients. A higher NY-ESO-1 score was associated with a younger age at diagnosis in the TNBC patients with NY-ESO-1 expression (p = 0.026). No differences in OS (p = 0.278) or PFS (p = 0.238) by NY-ESO-1 expression status were detected. Antibody responses to NY-ESO-1 were found in 73% of TNBC patients whose tumors were NY-ESO-1 positive. NY-ESO-1 positive patients had higher CD8 counts than negative patients (p = 0.018). Conclusion NY-ESO-1 is expressed in a substantial subset of TNBC patients and leads to a high humoral immune response in a large proportion of these individuals. Given these observations, patients with TNBC may benefit from targeted therapies directed against NY-ESO-1.

[1]  Y. Doki,et al.  A phase I study of vaccination with NY‐ESO‐1f peptide mixed with Picibanil OK‐432 and Montanide ISA‐51 in patients with cancers expressing the NY‐ESO‐1 antigen , 2011, International journal of cancer.

[2]  P. Watson,et al.  Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer , 2011, Breast Cancer Research.

[3]  J. Luketich,et al.  Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer. , 2011, The Journal of surgical research.

[4]  J. Wolchok,et al.  Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab , 2011, Proceedings of the National Academy of Sciences.

[5]  L. Old,et al.  Immunoediting and persistence of antigen-specific immunity in patients who have previously been vaccinated with NY-ESO-1 protein formulated in ISCOMATRIX™ , 2011, Cancer Immunology, Immunotherapy.

[6]  M. Campone,et al.  Antibody Responses to NY-ESO-1 in Primary Breast Cancer Identify a Subtype Target for Immunotherapy , 2011, PloS one.

[7]  Ian O Ellis,et al.  Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  A. Simpson,et al.  Multiple Cancer/Testis Antigens Are Preferentially Expressed in Hormone-Receptor Negative and High-Grade Breast Cancers , 2011, PloS one.

[9]  Jakić-Razumović Jasminka,et al.  High expression of MAGE-A10 cancer-testis antigen in triple-negative breast cancer , 2011, Medical Oncology.

[10]  A. Goldhirsch,et al.  Cancer-testis antigen expression in triple-negative breast cancer. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Shuji Ogino,et al.  Tumour‐infiltrating T‐cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review , 2010, The Journal of pathology.

[12]  D. Matei,et al.  A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum‐resistant, epithelial ovarian cancer , 2010, Cancer.

[13]  N. Halama,et al.  Seromic profiling of ovarian and pancreatic cancer , 2010, Proceedings of the National Academy of Sciences.

[14]  A. Simpson,et al.  CT-X antigen expression in human breast cancer , 2009, Proceedings of the National Academy of Sciences.

[15]  P. Sharma,et al.  NY-ESO-1 DNA Vaccine Induces T-Cell Responses That Are Suppressed by Regulatory T Cells , 2009, Clinical Cancer Research.

[16]  Andrew J. G. Simpson,et al.  CTdatabase: a knowledge-base of high-throughput and curated data on cancer-testis antigens , 2008, Nucleic Acids Res..

[17]  Oliver Hofmann,et al.  Genome-wide analysis of cancer/testis gene expression , 2008, Proceedings of the National Academy of Sciences.

[18]  K. Odunsi,et al.  Intertumor and Intratumor NY-ESO-1 Expression Heterogeneity Is Associated with Promoter-Specific and Global DNA Methylation Status in Ovarian Cancer , 2008, Clinical Cancer Research.

[19]  D. Getnet,et al.  LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. , 2007, The Journal of clinical investigation.

[20]  S. Narod,et al.  Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence , 2007, Clinical Cancer Research.

[21]  K. Odunsi,et al.  Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer , 2007, Proceedings of the National Academy of Sciences.

[22]  D. Jäger,et al.  NY‐ESO‐1 protein expression in primary breast carcinoma and metastases—correlation with CD8+ T‐cell and CD79a+ plasmacytic/B‐cell infiltration , 2007, International journal of cancer.

[23]  Katherine S Panageas,et al.  Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  D. Jäger,et al.  LUD 00-009: phase 1 study of intensive course immunization with NY-ESO-1 peptides in HLA-A2 positive patients with NY-ESO-1-expressing cancer. , 2007, Cancer immunity.

[25]  M. Nesline,et al.  Establishing a Cancer Center Data Bank and Biorepository for Multidisciplinary Research , 2006, Cancer Epidemiology Biomarkers & Prevention.

[26]  A. Qattan,et al.  The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. , 2006, Neoplasia.

[27]  M. Pfreundschuh,et al.  Prospective study on the expression of cancer testis genes and antibody responses in 100 consecutive patients with primary breast cancer , 2006, International journal of cancer.

[28]  Gerd Ritter,et al.  Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[29]  P. Parrilla,et al.  Antibody‐mediated signaling through PD‐1 costimulates T cells and enhances CD28‐dependent proliferation , 2005, European journal of immunology.

[30]  Lieping Chen,et al.  In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses , 2005, The Journal of experimental medicine.

[31]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[32]  G. Freeman,et al.  The B7 family revisited. , 2005, Annual review of immunology.

[33]  M. Monden,et al.  NY-ESO-1 Expression and Immunogenicity in Malignant and Benign Breast Tumors , 2004, Cancer Research.

[34]  Yao-Tseng Chen,et al.  NY-ESO-1 and LAGE-1 cancer-testis antigens are potential targets for immunotherapy in epithelial ovarian cancer. , 2003, Cancer research.

[35]  Yao-Tseng Chen,et al.  Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: Correlation with antibody responses , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[37]  F. Tanaka,et al.  Expression of multiple cancer-testis antigen genes in gastrointestinal and breast carcinomas , 2001, British Journal of Cancer.

[38]  N. Altorki,et al.  Immunohistochemical analysis of NY‐ESO‐1 antigen expression in normal and malignant human tissues , 2001, International journal of cancer.

[39]  D. Speiser,et al.  Naturally occurring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients. , 2000, Cancer research.

[40]  D. Jäger,et al.  Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Yao-Tseng Chen,et al.  Expression of multiple cancer/testis (CT) antigens in breast cancer and melanoma: Basis for polyvalent CT vaccine strategies , 1998, International journal of cancer.

[42]  L. Michaux,et al.  LAGE‐1, a new gene with tumor specificity , 1998, International journal of cancer.

[43]  Lloyd J. Old,et al.  A Survey of the Humoral Immune Response of Cancer Patients to a Panel of Human Tumor Antigens , 1998, The Journal of experimental medicine.

[44]  D. Jäger,et al.  Simultaneous Humoral and Cellular Immune Response against Cancer–Testis Antigen NY-ESO-1: Definition of Human Histocompatibility Leukocyte Antigen (HLA)-A2–binding Peptide Epitopes , 1998, The Journal of experimental medicine.

[45]  O. de Backer,et al.  The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[46]  A. Houghton.  Cancer antigens: immune recognition of self and altered self , 1994, The Journal of experimental medicine.

[47]  E. Nakayama,et al.  Effect of in vivo administration of Lyt antibodies. Lyt phenotype of T cells in lymphoid tissues and blocking of tumor rejection , 1985, The Journal of experimental medicine.

[48]  M. Arlen.  Tumor antigens. , 1981, The New England journal of medicine.