title: Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization.
abstract: Necrosis of tumor cells can activate both innate and adaptive antitumor immunity. However, there is little information on the effects of necrosis-inducing cancer treatments on tumor-specific T cell immune responses in humans. We studied the effects of a necrosis-inducing treatment (embolization) on anti-alpha-fetoprotein (AFP)-specific CD4(+) T cell responses in hepatocellular carcinoma (HCC) patients and controls using an array of AFP-derived peptides. In this study, we show that AFP-specific CD4(+) T cell responses to three immunodominant epitopes in HCC patients were significantly expanded during (p < 0.0001) and after embolization (p < 0.002). The development of higher frequencies of AFP-specific CD4(+) T cells after treatment were significantly associated with the induction of >50% necrosis of tumor and an improved clinical outcome (p < 0.007). In addition, we identified two novel HLA-DR-restricted AFP-derived CD4(+) T cell epitopes (AFP(137-145) and AFP(249-258)) and showed that the CD4(+) T cells recognizing these epitopes produce Th1 (IFN-gamma and TNF-alpha) but not Th2 (IL-5)-type cytokines. AFP(137-145)-, AFP(249-258)-, and AFP(364-373)-specific CD4(+) T cells were detected in HCC patients but not in patients with chronic liver diseases or healthy donors. In conclusion; our study shows that induction of tumor necrosis by a conventional cancer treatment can unmask tumor rejection Ag cell-mediated immunity and provides a rationale for combining embolization with immunotherapy in HCC patients.
authors.affiliation: Department of Medicine, University College London Institute of Hepatology, London.
authors.forename: Lakshmana
authors.initials: L
authors.lastname: Ayaru
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
authors.forename: Akeel
authors.initials: A
authors.lastname: Alisa
authors.forename: Ansar A
authors.initials: AA
authors.lastname: Pathan
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.forename: Brian
authors.initials: B
authors.lastname: Davidson
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Burroughs
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
authors.forename: Shahriar
authors.initials: S
authors.lastname: Behboudi
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis; D004621:Embolization, Therapeutic; D005260:Female; D006684:HLA-DR Antigens; D006801:Humans; D007109:Immunity; D016056:Immunodominant Epitopes; D008297:Male; D008875:Middle Aged; D009336:Necrosis / Q000209:etiology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D000509:alpha-Fetoproteins / Q000276:immunology*
chemical_list: D016207:Cytokines; D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D000509:alpha-Fetoproteins