title: Expansion of interferon-gamma-producing multifunctional CD4+ T-cells and dysfunctional CD8+ T-cells by glypican-3 peptide library in hepatocellular carcinoma patients.
abstract: Glypican-3 is a promising target for immunotherapy for hepatocellular carcinoma, but limited data exist regarding its immunogenicity in patients with diverse HLA types, immunogenicity for CD4(+) T-cells, and the impact of inhibitory co-stimulation on glypican-3-specific T-cells. Using a 15mer overlapping peptide library for glypican-3, PBMC from patients with HCC were assessed ex vivo and after short-term in vitro expansion for tumor antigen-specific T-cell responses with and without blockade of PD-1/PD-L1 and CTLA-4 signaling. Glypican-3-specific T-cells were undetectable ex vivo, but primarily IFNγ(+)TNFα(+) CD4(+) T-cells expanded with short-term in vitro stimulation in 10/19 (52%) patients. Glypican-3-specific CD8(+) T-cells predominantly produced TNFα, but did not secrete IFNγ nor degranulate. CTLA-4 and PD-1 blockade minimally impacted the cytokine secretion and proliferation of glypican-3-specific T-cells. These data suggest that CD8(+) T-cell-directed tumor vaccines in HCC may have limited potential for efficacy unless optimal co-stimulation conditions can be identified but CD4(+)-directed vaccines merit consideration.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, USA.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Rui Lin
authors.initials: RL
authors.lastname: Gao
authors.forename: Oluwasayo
authors.initials: O
authors.lastname: Adeyemo
authors.forename: Maxim
authors.initials: M
authors.lastname: Itkin
authors.forename: David E
authors.initials: DE
authors.lastname: Kaplan
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000628:therapy; D016022:Case-Control Studies; D048708:Cell Growth Processes / Q000276:immunology; D005434:Flow Cytometry; D053673:Glypicans / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D019151:Peptide Library; D010455:Peptides / Q000276:immunology / Q000494:pharmacology*
chemical_list: D053673:Glypicans; D015789:HLA-A2 Antigen; D019151:Peptide Library; D010455:Peptides; D007371:Interferon-gamma