CD137 and CD137 ligand constitutively coexpressed on human T and B leukemia cells signal proliferation and survival.
CD137, a member of the tumor necrosis factor receptor family, provides expansion and survival signal to T cells. Its ligand, CD137L, in addition to its ability to costimulate T cells, signals back into antigen presenting cells promoting their activation and differentiation. Recently, CD137 has been proposed as a therapeutic target to improve and sustain anticancer immune response. Several activated T leukemia and B lymphoma cell lines expressed CD137 or CD137L, respectively, and soluble CD137L has been found in sera of leukemia patients. However, the functionality and role of these costimulatory molecules in hematologic malignancies are until now unknown. Interestingly, we observed constitutive CD137 and CD137L coexpression on both human T and B leukemia cell lines. The constitutive CD137 expression on unstimulated T or B leukemia cells presents some differences compared to CD137 expressed on PMA/ionomycin-activated T leukemia cells. Surprisingly, in spite of the low expression level, both tumor CD137 and CD137L molecules signaled in T and B leukemia cells inducing proliferation and prolonging survival. In addition, CD137/CD137L system ligation opposed the anticancer drug cytotoxic effects, reducing the apoptotic DNA fragmentation and stimulating proliferation of doxorubicin-escaped leukemia cells. Although the role of leukemia CD137/CD137L system in vivo is unknown, these data suggest that these costimulatory molecules might confer an advantage to hematologic tumors promoting survival, sustaining cellular growth and contributing to drug resistance.
Palma
Carla
C
Department of Pharmacology, Menarini Ricerche SpA, Rome, Italy. pharmacology@menarini-ricerche.it
Binaschi
Monica
M
Bigioni
Mario
M
Maggi
Carlo Alberto
CA
Goso
Cristina
C
D053330:4-1BB Ligand; D015703:Antigens, CD / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015448:Leukemia, B-Cell / Q000378:metabolism* / Q000473:pathology; D015458:Leukemia, T-Cell / Q000378:metabolism* / Q000473:pathology; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053330:4-1BB Ligand; D015703:Antigens, CD; D000970:Antineoplastic Agents; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; C505974:TNFSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin