title: Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells.
abstract: T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan-A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T-cells in PBMC of melanoma patients. Here we analyzed the functionality of these T-cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease-free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.
authors.affiliation: Clinical Tumor Immune-Biology Unit, Ludwig Center for Cancer Research of the University of Lausanne, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgaertner
authors.forename: Camilla
authors.initials: C
authors.lastname: Jandus
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Rivals
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
authors.forename: Tanja
authors.initials: T
authors.lastname: Lövgren
authors.forename: Lukas
authors.initials: L
authors.lastname: Baitsch
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: Gregoire
authors.initials: G
authors.lastname: Berthod
authors.forename: Maurice
authors.initials: M
authors.lastname: Matter
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D017252:CD3 Complex / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007121:Immunocompetence; D058965:MART-1 Antigen / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D058965:MART-1 Antigen; C548667:MLANA protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; D048049:Extracellular Signal-Regulated MAP Kinases