title: Antitumor T cell responses in bladder cancer are directed against a limited set of antigens and are modulated by regulatory T cells and routine treatment approaches.
abstract: Regulatory T cells (Tregs) play a key role in cancer immune escape. We identified target antigens of spontaneous tumor-specific T cell responses in urothelial carcinoma (UC) and evaluated their modulation by treatment and Treg. We determined Treg target antigens in UC. Fifty-six UC and 13 control patients were prospectively enrolled. Blood was drawn before and after routine treatment. Changes in Treg frequency were measured by fluorescence cytometry and the T effector cell (Teff) response against a set of nine tumor-associated antigens (TAAs) was monitored with an interferon-gamma ELISpot. Antigen specificity of Treg was determined by their increased capacity to inhibit after TAA-specific activation the proliferation of an autologous T cell population. The highest difference in the overall response rate for the total T cell population was observed for epidermal growth factor receptor (EGFR) (UC: 23% and controls: 0%). After depleting Treg, also new york esophageal (NYES)O1 (19 and 0%) and MUC20 (27 and 0%) were more frequently recognized in UC patients. In metastasized patients, the TAA-directed T cell response was augmented by Treg depletion. Tumor resection seemed to diminish Treg suppression of TAA-specific immunity, whereas chemotherapy had no effect. We demonstrated the existence of TAA-specific Treg in UC, which share antigen specificities with Teff. The coexistence of TAA-specific Treg and Teff was very rare. Treg frequencies in the peripheral blood were not changed by therapy. In summary, we identified potentially immunologically relevant TAA in UC. TAA-specific T cell responses against these antigens are suppressed by Treg. We identified TAA-specific Treg in UC patients, which do not cooccur with TAA-specific Teff.
authors.affiliation: Department of Urology, Klinikum Rechts der Isar, Technische Universität München, München, Germany. t.horn@lrz.tum.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Horn
authors.forename: Jessica
authors.initials: J
authors.lastname: Grab
authors.forename: Julia
authors.initials: J
authors.lastname: Schusdziarra
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmid
authors.forename: Tobias
authors.initials: T
authors.lastname: Maurer
authors.forename: Roman
authors.initials: R
authors.lastname: Nawroth
authors.forename: Petra
authors.initials: P
authors.lastname: Wolf
authors.forename: Maria
authors.initials: M
authors.lastname: Pritsch
authors.forename: Jürgen E
authors.initials: JE
authors.lastname: Gschwend
authors.forename: Hubert R
authors.initials: HR
authors.lastname: Kübler
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D016022:Case-Control Studies; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation; D008297:Male; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014571:Urologic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy
chemical_list: D000951:Antigens, Neoplasm; D007371:Interferon-gamma
keywords: regulatory T cells; tumor-associated antigen; tumor-reactive T cells; urothelial cancer