Sunitinib impairs the proliferation and function of human peripheral T cell and prevents T-cell-mediated immune response in mice.
Sunitinib (sunitinib malate; SU11248; SUTENT) is a novel multi-targeted receptor tyrosine kinase inhibitor currently approved for the treatment of metastatic renal cell carcinoma. To analyze the possible use of this compound in combination with immunotherapeutic approaches, we investigated the effects of sunitinib on the human peripheral T cells and the induction of primary immune responses in mice. Sunitinib inhibited the proliferation of primary human T cells from normal healthy volunteers as well as from renal cell carcinoma (RCC) and other cancer patients. The inhibition was recoverable after drug withdrawal because sunitinib did not induce T-cell apoptosis even at 0.8 muM. In addition, sunitinib led to accumulation in G(0)/G(1) phase of the cell cycle, inhibition of cytokine production, downregulation of activation markers expression and blockade of Zap-70 signaling in the T cells. Sunitinib significantly reduced the ear swelling induced by picryl chloride in mice. In light of these findings, the effects of sunitinib on the immune system should be emphasized for the therapy of metastatic renal cell carcinoma patients to avoid the impairment of T lymphocytes.
Gu
Yanhong
Y
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University 22 Han Kou Road, Nanjing 210093, China.
Zhao
Wei
W
Meng
Fanyu
F
Qu
Bingqian
B
Zhu
Xu
X
Sun
Yang
Y
Shu
Yongqian
Y
Xu
Qiang
Q
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006651:Histocytochemistry; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D010853:Picryl Chloride / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D000077210:Sunitinib; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000970:Antineoplastic Agents; D016207:Cytokines; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib; D010853:Picryl Chloride