Inhibition of immune responses by Dasatinib may account for its different effects on neuroblastoma between in vitro and in vivo

Abstract

Nonreceptor tyrosine kinase Src is found to be overexpressed in many cancers and plays an important role in cancer formation, progression and metastasis via the activation of several downstream signal pathways and cytoskeleton.1-3 Overexpression of Src negative regulator csk suppresses tumor metastasis in a mouse colon cancer model.4 Thus, inhibition of Src could be used for the treatment of those cancers with overexpressed Src. Many small molecules have been developed for the purpose, and several agents are currently under clinical trials.1 Dasatinib is a second-generation Src inhibitor with stronger effect on cancer cells.5 Except Src, Dasatinib also inhibits other kinases or nonkinase proteins. However, its actual effect in cancer treatment still needs further investigation. The article “activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model” by Vitali et al. published in your journal is highly interesting. The study provides an important observation that Dasatinib strongly inhibits the growth of neuroblastoma cells and induces senescence and apoptosis in vitro. However, Dasatinib does not produce the expected effect in vivo. This important issue has to be further understood to improve clinical implication of Dasatinib. I think that this phenomenon may be explained by the inhibition of the immune system in vivo by Dasatinib via Src. Although overexpression of Src plays an important role in the pathogenesis of cancer, the normal expression of Src is necessary for the immune responses.6, 7 Immune responses are critical for surveillance and eradication of cancer cells. In the cancer treatment, weaken cancer cells need to be cleaned by immune cells. Thus, immunotherapy has been used to increase the effect of chemotherapy and reduce the dose of cytotoxicity drugs and therefore reduce their side effects.8 Many studies have demonstrated that inhibition of Src affects both innate and adaptive immune responses. Src has been demonstrated to be important in the activation of macrophage, dendritic cells and natural killer cells.7, 9 It has also been shown to control cytokine production such as production of TNF-alpha stimulated by LPS, which is inhibited by Dasatinib.10 Through DC and cytokine production, it can affect adaptive immunity. Evidence has shown the important role of Src in T-cell development.11 Indeed, Dasatinib has been shown to inhibit effector CD4+, CD8+ T-cells,12, 13 NK cells9 and CD4+ CD25+ regulatory T cells.14 A recent study has investigated Dasatinib for its immunosuppression effect in 16 CML patients at a dose of 140 mg/day.15 In these patients, Dasatinib has caused decreases in cell numbers of T-cells, B-cells and natural killer cells. The decreased immune responses caused by Dasatinib may be associated with observed increased infections and formation of skin cancer in Dasatinib-treated patients.15 It will be interesting to further examine the immune system in the model used by Vitali et al. The insight into immune responses altered by Dasatinib may have implications in the design of therapy regime either by adding immune therapy agents or reducing the dosage but used with other chemotherapy drugs so that the immune system is well maintained when aiming to weaken cancer cells by the inhibition of the Src signal pathway. Indeed, the combination therapy with cytotoxic agent has been used to achieve good outcome. The combination with immunotherapy may also produce better outcome. Yours sincerely, Jiezhong Chen.