Antibody-Targeted NY-ESO-1 to Mannose Receptor or DEC-205 In Vitro Elicits Dual Human CD8+ and CD4+ T Cell Responses with Broad Antigen Specificity

Immunization of cancer patients with vaccines containing full-length tumor Ags aims to elicit specific Abs and both CD4+ and CD8+ T cells. Vaccination with protein Ags, however, often elicits only CD4+ T cell responses without inducing Ag-specific CD8+ T cells, as exogenous protein is primarily presented to CD4+ T cells. Recent data revealed that Ab-mediated targeting of protein Ags to cell surface receptors on dendritic cells could enhance the induction of both CD4+ and CD8+ T cells. We investigated in this study if these observations were applicable to NY-ESO-1, a cancer-testis Ag widely used in clinical cancer vaccine trials. We generated two novel targeting proteins consisting of the full-length NY-ESO-1 fused to the C terminus of two human mAbs against the human mannose receptor and DEC-205, both internalizing molecules expressed on APC. These targeting proteins were evaluated for their ability to activate NY-ESO-1–specific human CD4+ and CD8+ T cells in vitro. Both targeted NY-ESO-1 proteins rapidly bound to their respective targets on APC. Whereas nontargeted and Ab-targeted NY-ESO-1 proteins similarly activated CD4+ T cells, cross-presentation to CD8+ T cells was only efficiently induced by targeted NY-ESO-1. In addition, both mannose receptor and DEC-205 targeting elicited specific CD4+ and CD8+ T cells from PBLs of cancer patients. Receptor-specific delivery of NY-ESO-1 to APC appears to be a promising vaccination strategy to efficiently generate integrated and broad Ag-specific immune responses against NY-ESO-1 in cancer patients.

[1]  A. Ochsenbein,et al.  CTL induction by cross‐priming is restricted to immunodominant epitopes , 2009, European journal of immunology.

[2]  P. Saunders,et al.  Proliferation of uterine natural killer cells is induced by human chorionic gonadotropin and mediated via the mannose receptor. , 2009, Endocrinology.

[3]  P. Sharma,et al.  Immune Responses Detected in Urothelial Carcinoma Patients After Vaccination With NY-ESO-1 Protein Plus BCG and GM-CSF , 2008, Journal of immunotherapy.

[4]  S. Adams,et al.  Immunization of Malignant Melanoma Patients with Full-Length NY-ESO-1 Protein Using TLR7 Agonist Imiquimod as Vaccine Adjuvant1 , 2008, The Journal of Immunology.

[5]  K. Odunsi,et al.  Recognition of naturally processed and ovarian cancer reactive CD8+ T cell epitopes within a promiscuous HLA class II T-helper region of NY-ESO-1 , 2008, Cancer Immunology, Immunotherapy.

[6]  C. Bokemeyer,et al.  Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming , 2008, Proceedings of the National Academy of Sciences.

[7]  L. Old,et al.  Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector. , 2008, Blood.

[8]  Carl G. Figdor,et al.  Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting , 2007, Nature Reviews Immunology.

[9]  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.

[10]  S. Vogel,et al.  Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming , 2007, Proceedings of the National Academy of Sciences.

[11]  L. Vitale,et al.  Antigenic Targeting of the Human Mannose Receptor Induces Tumor Immunity1 , 2007, The Journal of Immunology.

[12]  S. Hue,et al.  Altered expression and endocytic function of CD205 in human dendritic cells, and detection of a CD205–DCL‐1 fusion protein upon dendritic cell maturation , 2007, Immunology.

[13]  P. Wallace,et al.  Toll-like receptor activation enhances cell-mediated immunity induced by an antibody vaccine targeting human dendritic cells , 2007, Journal of Translational Medicine.

[14]  M. Carrington,et al.  DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes , 2007, Proceedings of the National Academy of Sciences.

[15]  D. Jäger,et al.  Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients , 2006, Proceedings of the National Academy of Sciences.

[16]  A. Belldegrun,et al.  Dendritic Cell Surface Calreticulin Is a Receptor for NY-ESO-1: Direct Interactions between Tumor-Associated Antigen and the Innate Immune System1 , 2006, The Journal of Immunology.

[17]  Masato Kato,et al.  Expression of human DEC-205 (CD205) multilectin receptor on leukocytes. , 2006, International immunology.

[18]  K. Odunsi,et al.  Influence of CD4+CD25+ Regulatory T Cells on Low/High-Avidity CD4+ T Cells following Peptide Vaccination1 , 2006, The Journal of Immunology.

[19]  R. Steinman,et al.  Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses , 2006, The Journal of experimental medicine.

[20]  D. Valmori,et al.  Distinct Structural TCR Repertoires in Naturally Occurring Versus Vaccine-Induced CD8+ T-Cell Responses to the Tumor-Specific Antigen NY-ESO-1 , 2005, Journal of immunotherapy.

[21]  Yao-Tseng Chen,et al.  IFN-gamma enables cross-presentation of exogenous protein antigen in human Langerhans cells by potentiating maturation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  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.

[23]  N. Brouwenstijn,et al.  Antigen Bias in T Cell Cross-Priming , 2004, Science.

[24]  J. Connolly,et al.  A Novel Human Cancer Vaccine Elicits Cellular Responses to the Tumor-Associated Antigen, Human Chorionic Gonadotropin β , 2004, Clinical Cancer Research.

[25]  R. Steinman,et al.  In Vivo Targeting of Antigens to Maturing Dendritic Cells via the DEC-205 Receptor Improves T Cell Vaccination , 2004, The Journal of experimental medicine.

[26]  J. Connolly,et al.  Mannose Receptor Targeting of Tumor Antigen pmel17 to Human Dendritic Cells Directs Anti-Melanoma T Cell Responses via Multiple HLA Molecules , 2004, The Journal of Immunology.

[27]  V. Reuter,et al.  Frequency of NY-ESO-1 and LAGE-1 expression in bladder cancer and evidence of a new NY-ESO-1 T-cell epitope in a patient with bladder cancer. , 2003, Cancer immunity.

[28]  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.

[29]  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.

[30]  D. Atanackovic,et al.  Monitoring CD4+ T cell responses against viral and tumor antigens using T cells as novel target APC. , 2003, Journal of immunological methods.

[31]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[32]  I. Mellman,et al.  Differential presentation of a soluble exogenous tumor antigen, NY-ESO-1, by distinct human dendritic cell populations , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Michel C. Nussenzweig,et al.  Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo , 2001, The Journal of experimental medicine.

[34]  V. Cerundolo,et al.  Strategy for monitoring T cell responses to NY-ESO-1 in patients with any HLA class I allele. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[35]  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.

[36]  Richard A. Flavell,et al.  Help for cytotoxic-T-cell responses is mediated by CD40 signalling , 1998, Nature.

[37]  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.

[38]  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.

[39]  Yao-Tseng Chen,et al.  A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Huszar,et al.  Antigen-specific human antibodies from mice comprising four distinct genetic modifications , 1994, Nature.

[41]  Y. Doki,et al.  T cell immunomonitoring and tumor responses in patients immunized with a complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein. , 2007, Cancer immunity.

[42]  Yao-Tseng Chen,et al.  NY-ESO-1: review of an immunogenic tumor antigen. , 2006, Advances in cancer research.

[43]  K. Odunsi,et al.  Th1/Th2 CD4+ T cell responses against NY-ESO-1 in HLA-DPB1*0401/0402 patients with epithelial ovarian cancer. , 2004, Cancer immunity.