In vitro and in vivo antitumor properties of a T-cell clone generated from murine tumor-infiltrating lymphocytes.
We have shown that a T-cell clone derived from murine tumor-infiltrating lymphocytes (TILs) can be established that mediates in vitro and in vivo antitumor effects. Utilizing this clone as a model, we examined the effect of cytokines on T-cell antitumor effector mechanisms in vitro and in vivo. This clone, termed BF-1, was generated by limiting dilution culture of a freshly excised MC-38 tumor, growing it in low levels of interleukin-2 (IL-2), and has been maintained for over 600 days. This clone became specifically cytotoxic for the MC-38 tumor during its first 100 days of culture. Pretreatment of the parental MC-38 tumor cell line with tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) increased its susceptibility to lysis by the BF-1 TIL line, but not to lysis by lymphokine-activated killer cells, in in vitro cytotoxicity assays. This increased susceptibility of the cytokine-pretreated targets was restricted to the parental tumor (MC-38), since similar pretreatment of MCA-102, MCA-105, or MCA-106 tumors did not render them susceptible to lysis by BF-1 TILs. This increased sensitivity to lysis in vitro was not the result of a change in the expression of major histocompatibility complex class I molecules. In experiments testing the ability of TILs to treat established lung metastases, the combination of TNF, IFN-gamma, IL-2, and TILs was shown to increase significantly the antitumor properties of this therapy when compared to TILs and IL-2. This result demonstrates that combinations of lymphokines, which when administered alone do not affect micrometastatic tumor burdens (TNF, IFN-gamma), can synergize with cellular immunotherapy in the treatment of established tumor burdens and may have applicabilities to the treatment of cancer in humans.
Fox
B A
BA
Surgery Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland.
Spiess
P J
PJ
Kasid
A
A
Puri
R
R
Mulé
J J
JJ
Weber
J S
JS
Rosenberg
S A
SA
D000230:Adenocarcinoma / Q000276:immunology* / Q000628:therapy; D000818:Animals; D002999:Clone Cells / Q000276:immunology; D003131:Combined Modality Therapy; D016207:Cytokines / Q000627:therapeutic use; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000502:physiology; D015151:Immunoblotting; D007371:Interferon-gamma / Q000627:therapeutic use; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma