T-cell-receptor engagement and tumor ICAM-1 up-regulation are required to by-pass low susceptibility of melanoma cells to autologous CTL-mediated lysis.
Tumor-specific and non-specific CD3+, TcR alpha beta+, CD8+ cytotoxic T-cell (CTL) clones, isolated from tumor-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) of a melanoma patient and allogeneic LAK cells, were used to investigate the requirements for bypassing the low lysability of some melanoma clones derived from an s.c. metastasis from which highly lysable clones were also obtained. Cytofluorimetric analysis showed that all melanoma clones expressed ICAM-1, although to different extents, reaching a 10-fold difference in fluorescence units, while HLA class-I antigens were similarly expressed. The differences in expression of ICAM-1 among tumor clones correlated with differences in lysability, by both specific and non-specific CTL, but were not large enough to affect lymphocyte-tumor conjugate formation. Cytokine- or gene-transfer-mediated up-regulation of ICAM-1 did not induce de novo lysis of ICAM-1low tumor cells; however, it markedly enhanced a low level of killing of the same cells by tumor-specific, TcR-dependent and HLA-restricted CTL clones but not by non-specific, TcR-independent effectors. In addition, lysis of melanoma clones by any effector was similarly inhibited by anti-ICAM-1 and anti-LFA-1 antibodies. This indicates that by-pass of low lysability of ICAM-1low melanoma clones by CTL clones, after ICAM-1 up-regulation, is possible only if simultaneous LFA-1 and TcR engagement takes place. In addition, these results suggest that the constitutive high level of expression of ICAM-1 on the subset of ICAM-1high melanoma cells must be only one of the factors contributing to the high lysability of these cells by any effector.
Anichini
A
A
Division of Experimental Oncology D, Istituto Nazionale Tumori, Milan, Italy.
Mortarini
R
R
Alberti
S
S
Mantovani
A
A
Parmiani
G
G
D015815:Cell Adhesion Molecules / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002999:Clone Cells; D016207:Cytokines / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D008285:Major Histocompatibility Complex / Q000502:physiology; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D012680:Sensitivity and Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D015815:Cell Adhesion Molecules; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1