Differential regulation by interleukin-4 and interferon-gamma of an autologous melanoma-specific cytotoxic T-cell clone and the tumor-infiltrating lymphocytes from which it was established.
To investigate the specificity of human tumor-infiltrating lymphocytes (TIL) against autologous tumors, TIL from five metastatic melanoma patients were expanded with rIL-2 and assessed for cytotoxicity in chromium release assays. TIL from a patient showing preferential cytotoxicity against autologous melanoma cells were further analysed. TIL were cloned by limiting dilution. Four out of 27 clones showed substantial cytotoxicity against autologous melanoma and one clone, designated as No. 8a-5 (CD3+, CD4-, CD8+, CD56-), selectively killed autologous melanoma but did not kill six different allogeneic melanoma, K562, or autologous or allogeneic Con A lymphoblast targets. Cytotoxicity of No. 8a-5 cells was inhibited by anti-HLA class I MAb (w6/32), by anti-beta 2-microglobulin MAb, and by anti-CD3 (OKT3) MAb, suggesting that the specific cytotoxicity was HLA class I-restricted and that the clone utilized the T-cell receptor complex for recognition of targets. Pretreatment with rIFN-gamma increased the sensitivity of autologous melanoma targets to lysis by No. 8a-5 cells. Exogenous rIL-4 enhanced [3H]TdR incorporation by these TIL. In contrast, rIFN-gamma reduced the sensitivity of the autologous melanoma to lysis by uncloned TIL, and rIL-4 suppressed the cytotoxicity and cell proliferation of uncloned TIL. These results indicate that both specific and non-specific cytotoxic cells can be developed from the same TIL and that these can be differentially regulated.
Yamada
T
T
Division of Surgical Oncology, UCLA School of Medicine 90024.
Holmes
E C
EC
Golub
S H
SH
D000911:Antibodies, Monoclonal / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D010641:Phenotype; D011994:Recombinant Proteins
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma