title: Interleukin 2 restores CD3-zeta chain expression but fails to generate tumour-specific lytic activity in tumour-infiltrating lymphocytes derived from human colorectal hepatic metastases.
abstract: Metastatic colorectal cancer is usually progressive despite infiltration of the tumours by T lymphocytes, suggesting that these tumour-infiltrating lymphocytes (TILs) are functionally deficient. Recently, TILs from other tumours have been shown to express reduced levels of the T-cell receptor signal-transducing CD3-zeta chain. We were interested to determine whether a similar abnormality existed in TILs from human colorectal hepatic metastasis (CHM) and, if so, whether correcting the abnormality in vitro would restore anti-tumour activity and provide support for the development of immunotherapy for colorectal hepatic metastases. Twelve of 19 TILs from colorectal hepatic metastases were successfully expanded in vitro in high-dose recombinant interleukin 2 (rlL-2) and their specific anti-tumour cytolytic activity was determined. CD3-positive (CD3+) TILs were HLA-Drhigh and CD69high, suggesting that they had been activated by exposure to antigen but expressed low levels of CD25, CD71 and the nuclear proliferation antigen Ki-67. Furthermore, they showed reduced expression of CD3-zeta compared with autologous peripheral blood T cells (PBTs) and failed to proliferate in the absence of high-dose rIL-2. Expansion of TILs in rIL-2 resulted in restoration of CD3-zeta expression and the ability to lyse K562 and Daudi cells but not autologous tumour cells. The absence of autologous tumour-specific cytolytic T-cell (CTL) activity may be due to the poor immunogenicity of colorectal tumour cells, which we found expressed only low levels of MHC I antigens and CD54 and failed to express MHC II antigens or the co-stimulatory molecules CD80, CD86 or CD106. The inability of rIL-2 to generate tumour-specific CTLs despite restoration of CD3-zeta expression and the presence of an intact lytic mechanism suggests that successful immunotherapy may require the development of strategies to increase the immunogenicity of this tumour.
authors.affiliation: Liver Research Laboratories, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: K F
authors.initials: KF
authors.lastname: Yoong
authors.forename: D H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; D007376:Interleukin-2; D009363:Neoplasm Proteins