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Sunitinib impairs the proliferation and function of human peripheral T cell and prevents T-cell-mediated immune
Yanhong Gu1, Wei Zhao, Fanyu Meng
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University 22 Han Kou Road, Nanjing 210093, China.
Abstract:
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.
Insights
Sunitinib, a cancer drug, inhibits T-cell proliferation and immune responses. This effect is reversible and does not cause T-cell death, suggesting careful consideration for cancer patients undergoing immunotherapy.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Sunitinib is an approved multi-targeted receptor tyrosine kinase inhibitor for metastatic renal cell carcinoma.
- Investigating sunitinib's impact on T cells is crucial for understanding its combination potential with immunotherapy.
Purpose of the Study:
- To analyze the effects of sunitinib on human peripheral T cells.
- To evaluate the induction of primary immune responses in mice treated with sunitinib.
Main Methods:
- Assessed sunitinib's impact on T-cell proliferation and apoptosis in vitro.
- Analyzed cell cycle, cytokine production, activation markers, and Zap-70 signaling in T cells.
- Evaluated sunitinib's effect on a contact hypersensitivity response in mice.
Main Results:
- Sunitinib inhibited T-cell proliferation across healthy donors, RCC, and other cancer patients.
- Inhibition was reversible, with no observed T-cell apoptosis.
- Sunitinib caused G(0)/G(1) cell cycle arrest, reduced cytokine production, downregulated activation markers, and blocked Zap-70 signaling.
- A significant reduction in mouse ear swelling was observed.
Conclusions:
- Sunitinib exhibits immunomodulatory effects by inhibiting T-cell proliferation and function.
- These findings highlight the importance of considering sunitinib's impact on T lymphocytes in metastatic renal cell carcinoma treatment.
- Further research is needed to optimize combination therapies involving sunitinib and immunotherapy.
