T-Cell Receptor Repertoire in Colorectal Adenocarcinoma Patients with Hepatic Metastases and Its Changes Induced by Preoperative Adjuvant Interleukin-2 Therapy

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) Va and V|3 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 Va and V(3 gene segment subfamily specificities in tumor hepatic tissue and blood of patients undergoing hepatic resection. In addition, we found that some Va and Vp 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.