A nonimmunogenic sarcoma transduced with the cDNA for interferon gamma elicits CD8+ T cells against the wild-type tumor: correlation with antigen presentation capability.
To be recognized by CD8+ T lymphocytes, target cells must process and present peptide antigens in the context of major histocompatibility complex (MHC) class I molecules. The nonimmunogenic, low class I-expressing, methylcholanthrene (MCA)-induced murine sarcoma cell line, MCA 101, is a poor presenter of endogenously generated viral antigens to specific CD8+ T lymphocytes and cannot be used to generate tumor infiltrating lymphocytes (TIL). Since interferon gamma (IFN-gamma) has been shown to upregulate three sets of molecules important for antigen processing and presentation, we retrovirally transduced wild-type MCA 101 (101.WT) tumor with the mIFN-gamma cDNA to create the 101.NAT cell line. Unlike 101.WT, some clones of retrovirally transduced 101.NAT tumor expressed high levels of class I, and could be used to generate CD8+ TIL. More importantly, these TIL were therapeutic in vivo against established pulmonary metastases from the wild-type tumor. Although not uniformly cytotoxic amongst several separate cultures, these TIL did specifically release cytokines (IFN-gamma and tumor necrosis factor-alpha) in response to 101.WT targets. 101.WT's antigen presentation deficit was also reversed by gene modification with mIFN-gamma cDNA. 101.NAT had a greatly improved capacity to present viral antigens to CD8+ cytotoxic T lymphocytes. These findings show that a nonimmunogenic tumor, incapable of generating a CD8+ T cell immune response, could be gene-modified to generate a therapeutically useful immune response against the wild-type tumor. This strategy may be useful in developing treatments for tumor histologies not thought to be susceptible to T cell-based immunotherapy.
Restifo
N P
NP
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Spiess
P J
PJ
Karp
S E
SE
Mulé
J J
JJ
Rosenberg
S A
SA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D008979:Moloney murine leukemia virus / Q000235:genetics; D011401:Promoter Regions, Genetic; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016827:CD8 Antigens; D014409:Tumor Necrosis Factor-alpha; D008748:Methylcholanthrene; D007371:Interferon-gamma; D013937:Thymidine Kinase