title: IL-18 paradox in pancreatic carcinoma: elevated serum levels of free IL-18 are correlated with poor survival.
abstract: The role of the proinflammatory interleukin (IL)-18 in cancer progression remains controversial; we thus examined the hypothesis that impaired antitumor immune response in pancreatic carcinoma patients is related to elevated levels of its natural inhibitor IL-18 binding protein (BP) and/or to alteration in the IL-18 receptor complex expression and function. IL-18 and IL-18 binding protein isoform a (BPa) was assessed in pancreatic carcinoma patients at various disease stages, and after surgery/chemotherapy; free bioactive IL-18 concentrations were calculated. IL-18 receptor complex expression in lymphocyte subsets was analyzed and signaling function was assessed versus healthy donors. Carcinoma cells exhibited below normal IL-18BPa expression and above normal IL-18 expression. Circulating IL-18BPa and IL-18 were above controls. Unexpectedly, free unbound IL-18 serum levels were correlated with disease severity and poor survival. IL-18BPa levels were unchanged by surgery but free IL-18 levels were elevated. Gemcitabine with 5-fluorouracil or oxaliplatin, but not alone, increased IL-18 and free IL-18 levels statistically significantly, without affecting IL-18BPa. Spontaneous/induced IL-18 receptor alpha and receptor beta expression in peripheral blood lymphocyte subsets from patients with advanced disease were near-normal, although CD4+ and CD8+ cells were fewer in percentage, and fully functional in inducing interferon-gamma. IL-18 is proposed as novel adjuvant cancer therapy, but free IL-18 levels are increased in the blood of pancreatic carcinoma patients, despite elevated IL-18BP levels, and are associated with poor survival; this highlights recent experimental insights into the prometastatic and proangiogenic effects of IL-18, and suggests that careful preclinical studies are needed to determine the proper application of IL-18 in cancer therapy.
authors.affiliation: Department of Clinical Physiopathology and Research Center on Experimental Medicine (CeRMS), University of Turin, Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Carbone
authors.forename: Barbara
authors.initials: B
authors.lastname: Vizio
authors.forename: Anna
authors.initials: A
authors.lastname: Novarino
authors.forename: Francesco Angelo
authors.initials: FA
authors.lastname: Mauri
authors.forename: Massimo
authors.initials: M
authors.lastname: Geuna
authors.forename: Carlo
authors.initials: C
authors.lastname: Robino
authors.forename: Gabriele
authors.initials: G
authors.lastname: Brondino
authors.forename: Adriana
authors.initials: A
authors.lastname: Prati
authors.forename: Alice
authors.initials: A
authors.lastname: Giacobino
authors.forename: Donata
authors.initials: D
authors.lastname: Campra
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
authors.forename: Gian Ruggero
authors.initials: GR
authors.lastname: Fronda
authors.forename: Libero
authors.initials: L
authors.lastname: Ciuffreda
authors.forename: Graziella
authors.initials: G
authors.lastname: Bellone
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000188:drug therapy / Q000401:mortality*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D007371:Interferon-gamma / Q000097:blood; D020382:Interleukin-18 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000401:mortality*; D053724:Receptors, Interleukin-18 / Q000276:immunology / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D009944:Organoplatinum Compounds; D053724:Receptors, Interleukin-18; C118370:interleukin-18 binding protein; D000077150:Oxaliplatin; D003841:Deoxycytidine; D007371:Interferon-gamma; D005472:Fluorouracil; D000093542:Gemcitabine