ALTERATIONS IN THE SIGNAL-TRANSDUCING MOLECULES OF T-CELLS AND NK CELLS IN COLORECTAL TUMOR-INFILTRATING, GUT MUCOSAL AND PERIPHERAL LYMPHOCYTES - CORRELATION WITH THE STAGE OF THE DISEASE

T cells from mice bearing an experimental colon carcinoma, and from pa tients with colorectal and renal carcinomas, have atypical T-cell rece ptors (TCR). In the present study, further characterization of modulat ions in CD3- and CD16-associated zeta chain in peripheral blood lympho cytes (PBL) and tumorinfiltrating lymphocytes (TIL) from colorectal ca rcinomas was performed. Relative to PBL, the percentage of natural kil ler (NK) cells among fresh TIL was reduced, while a higher proportion of T cells expressing HLA-DR was found. As previously reported, we fou nd significantly reduced levels of the CD3- and CD16-associated zeta c hain in TIL and, to a lesser extent, also in patients' PBL. Levels of zeta chain in T and NK cells from non-cancerous colorectal tissue from patients were lower than in PBL but higher than in TIL, with a direct relationship between levels of this signal-transducing molecule and t he distance from the tumor. In addition, zeta levels correlated with t he Dukes' stage of the disease, since PBL from patients with lymph-nod e involvement or distant organ metastases (Dukes' stages C and D) had significantly less CD3 zeta than patients with localized disease (stag es A and B). Patients' T cells also had decreased levels of cell-surfa ce and cytoplasmic CD3 epsilon. We also observed reduced levels of the TCR accessory molecules CD4 and CD8, mainly on TIL but to a lesser ex tent also on patients' PBL. Biochemical analysis of anti-CD3 epsilon-i mmunoprecipitated TCR complexes demonstrated that the CD3 complex was not associated with the zeta chain, either on TIL or on PBL or on lymp hocytes from non-cancerous colon tissue, suggesting a defect in the as sembly of the TCR complex. Following several days of in vitro culture with recombinant interleukin-2 and phytohemagglutinin, anti-CD3 or ant i-CD2 monoclonal antibodies (MAbs), levels of CD3 zeta chain as well a s of cell surface CD3 epsilon were normalized. Our findings suggest an abnormal expression as well as assembly of several different signal-t ransducing molecules of T cells and NK cells, which correlate with the stage of the disease in patients with colorectal carcinomas. (C) 1995 Wiley-Liss, Inc.