Enhancement of IL-2-induced cytotoxicity by interferon-alpha in renal cell carcinoma.
Metastatic renal cell carcinoma (mRCC) treatment consists of molecular targeted agents and cytokines that have fundamentally different mechanisms of action. Clinical responses also differ; complete response is rare with molecular targeted agents but is sometimes achieved with cytokine therapies. Because of the relatively high efficacy of combination therapy with low-dose interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) against mRCC, it is important to reevaluate cytokine therapies in vitro. Here, we show that when IL-2 is administered in combination with IFN-alpha, a stronger cytotoxic effect of PBMCs on RCC cell lines is observed than when IL-2 is administered alone. The upregulation of TNF-related apoptosis-inducing ligand on NK cell by IL-2 and suppression of regulatory T cells (Tregs) by IFN-alpha were recognized at the same time when cytotoxicity of peripheral blood mononuclear cells (PBMCs) was enhanced. IL-2 is known to activate natural killer cell cytotoxicity; however, IL-2 also stimulates Treg expansion, which enhances immunosuppression. On the other hand, IFN-alpha negatively regulates Treg cells, thereby increasing the function of immune effector cells. Our in vitro results may explain, at least in part, the clinical efficacy of combination low-dose IL-2 and IFN-alpha therapy against mRCC.
Division of Urology, Showa University, Tokyo, Japan. naoemichio@yahoo.co.jp
Michio
M
Naoe
Yoshio
Y
Ogawa
Yuki
Y
Hasebe
Jun
J
Morita
Takeshi
T
Shichijo
Atsushi
A
Igarashi
Kozo
K
Fuji
Sanju
S
Iwamoto
Toru
T
Suzuki
Shuji
S
Terao
D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D007694:Killer Cells, Natural / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology
D016898:Interferon-alpha; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand