title: Enhancing whole-tumor cell vaccination by engaging innate immune system through NY-ESO-1/dendritic cell interactions.
abstract: NY-ESO-1 is a cancer/germline antigen (Ag) with distinctively strong immunogenicity. We have previously demonstrated that NY-ESO-1 serves as an endogenous adjuvant by engaging dendritic cell (DC)-surface receptors of calreticulin (CRT) and toll-like receptor (TLR) 4. In the present study, NY-ESO-1 was investigated for its immunomodulatory roles as a molecular adjuvant in whole-tumor cell vaccines using the Renca kidney cancer model. Renca cells were genetically engineered to express NY-ESO-1 on the cell surface to enhance direct interactions with DC. The effect of ectopic cell-surface expression of NY-ESO-1 was investigated on tumor immunogenicity, DC activation, cytotoxic T lymphocytes against model tumor-associated Ags, and the effectiveness of the modified tumor cells as a therapeutic whole-cell vaccine. Cell-surface expression of NY-ESO-1 was able to reduce the tumor growth of Renca cells in BALB/c mice, although the modification did not alter cell proliferation rate in vitro. Directly engaging the innate immune system through NY-ESO-1 facilitated the interaction of tumor cells with DC, leading to enhanced DC activation and subsequent tumor-specific T-cell priming. When used as a therapeutic whole-cell vaccine, Renca cells with NY-ESO-1 on the surface mediated stronger inhibitory effects on tumor growth and metastasis compared with parental Renca or Renca cells expressing a control protein GFP on the surface. Augmented antitumor efficacy correlated with increased CD8 T-cell infiltration into tumors and decreased myeloid-derived suppressor cells and regulatory T cells in the spleen. As a cancer/germline Ag and as an immunomodulatory adjuvant through engaging innate immune receptors, NY-ESO-1 offers a unique opportunity for improved whole-tumor cell vaccinations upon the classic GM-CSF-engineered cell vaccines.
authors.affiliation: Departments of *Urology †Medicine-Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Le
authors.initials: L
authors.lastname: Xu
authors.forename: Junying
authors.initials: J
authors.lastname: Zheng
authors.forename: David H
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Quang T
authors.initials: QT
authors.lastname: Luong
authors.forename: Gang
authors.initials: G
authors.lastname: Zeng
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D002450:Cell Communication / Q000235:genetics; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D019076:Transgenes / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D008565:Membrane Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor