IL-18 paradox in pancreatic carcinoma: elevated serum levels of free IL-18 are correlated with poor survival.
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.
Carbone
Anna
A
Department of Clinical Physiopathology and Research Center on Experimental Medicine (CeRMS), University of Turin, Turin, Italy.
Vizio
Barbara
B
Novarino
Anna
A
Mauri
Francesco Angelo
FA
Geuna
Massimo
M
Robino
Carlo
C
Brondino
Gabriele
G
Prati
Adriana
A
Giacobino
Alice
A
Campra
Donata
D
Chiarle
Roberto
R
Fronda
Gian Ruggero
GR
Ciuffreda
Libero
L
Bellone
Graziella
G
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
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