title: T-cell receptor repertoire in colorectal adenocarcinoma patients with hepatic metastases and its changes induced by preoperative adjuvant interleukin-2 therapy.
abstract: The liver is the primary site for colorectal metastases and hepatic resection often fails to cure these patients. Little is known about T-cell immune response in these patients or its changes after interleukin-2 (IL-2) infusion. Using polymerase chain reaction methodology, we investigated T-cell receptor (TCR) V alpha and V beta gene segment subfamily usage in tumor, hepatic tissue, and blood of six patients undergoing hepatic resection and, in addition, in six patients receiving preoperative adjuvant IL-2 therapy (randomized phase I trial). The objectives were (a) to analyze the TCR repertoire in patients undergoing hepatic resection (without IL-2), (b) to analyze the TCR repertoire in patients undergoing hepatic resection after IL-2 therapy, (c) to analyze the effects of preoperative IL-2 infusion on the tumor-infiltrating lymphocyte (TIL) TCR repertoire by comparing TCR V gene segment usage in IL-2-treated versus nontreated patients, and (d) to analyze the effect of IL-2 infusion on the peripheral blood mononuclear cell (PBMC) TCR repertoire by comparing TCR V gene segment expression in pre- versus posttreatment PBMC of IL-2-treated patients. With regard to the first objective, we observed an unrestricted use of V alpha and V beta gene segment subfamily specificities in tumor hepatic tissue and blood of patients undergoing hepatic resection. In addition, we found that some V alpha and V beta specificities were overexpressed in tumor compared with hepatic tissue and blood, suggesting that the corresponding T-cell subpopulations were expanded at the tumor site. In IL-2-treated patients, in whom the tumor and liver were heavily infiltrated by T lymphocytes, the TIL TCR repertoire was also highly diverse and roughly similar to that detected in hepatic tissue and blood, except for a few overexpressions. To analyze the effect of IL-2 on TIL, we next compared the data obtained in IL-2-treated versus nontreated patients. No significant difference between the two groups was observed. Finally, no major changes in the PBMC TCR repertoire were found after IL-2 infusion. Further studies are needed to identify discrete T-cell subpopulations in these patients that may participate in either tumor immune surveillance or active immunotherapy mechanisms triggered by systemic IL-2 infusion.
authors.affiliation: Unité d'Immunologie Cellulaire, INSERM U333, Institut Gustave Roussy, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Savelieva
authors.forename: F
authors.initials: F
authors.lastname: Farace
authors.forename: E
authors.initials: E
authors.lastname: Angevin
authors.forename: D
authors.initials: D
authors.lastname: Elias
authors.forename: B
authors.initials: B
authors.lastname: Escudier
authors.forename: P
authors.initials: P
authors.lastname: Duvillard
authors.forename: T
authors.initials: T
authors.lastname: Hercend
authors.forename: F
authors.initials: F
authors.lastname: Triebel
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000503:physiopathology* / Q000628:therapy; D000368:Aged; D015179:Colorectal Neoplasms / Q000097:blood / Q000503:physiopathology* / Q000628:therapy; D005260:Female; D006498:Hepatectomy; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000097:blood / Q000556:secondary* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011300:Preoperative Care; D012313:RNA / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000032:analysis* / Q000235:genetics
chemical_list: D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D012313:RNA