TY - JOUR
T1 - Therapeutic activity of sunitinib for Her2/neu induced mammary cancer in FVB mice
AU - Abe, Fuminori
AU - Younos, Ibrahim
AU - Westphal, Sherry
AU - Samson, Holly
AU - Scholar, Eric
AU - Dafferner, Alicia
AU - Hoke, Traci A.
AU - Talmadge, James E.
N1 - Funding Information:
Supported in part by funding from NIH grant 5 RO1 AT001739 , Eppley Cancer Center and Nebraska DHHS LB506 . The authors would like to thank Ms. Jill Hallgren for typing of the manuscript.
PY - 2010/1
Y1 - 2010/1
N2 - Mouse mammary tumor virus-Neu (MMTV/neu) transgenic mice on an FVB-background (FVB-neuN) have increased numbers of myeloid derived suppressor cells (MDSCs) and regulatory T-cells (T-regs) in the spleen during mammary tumor induction and progression. Using this transgenic tumor model, we assessed the therapeutic activity of sunitinib, a multi-targeted, tyrosine kinase (TK) inhibitor and its effects on immune-regulatory cells. Our preliminary results show that sunitinib at 40 mg/kg/day, p.o. (per os), delayed the time to tumor induction and reduced the incidence and growth of tumors in FVB-neuN mice. In association with its therapeutic activity, sunitinib reduced the absolute number of splenic T-reg cells (CD4+CD25+CD62L+) and MDSCs (CD11b+Gr1+) that were increased during tumor progression with less activity in mice with gross tumors. A significant decrease in the absolute number of splenic T-regs, dendritic cells (DCs), MDSCs and hematopoietic progenitors (Lin-Sca1+CD90dull) was observed following sunitinib treatment. The frequency of splenic T-regs and hematopoietic progenitors, but not MDSCs was also reduced by sunitinib treatment. Additionally immune-regulatory cytokines and enzymes were down regulated by sunitinib treatment, including TGFβ and NOS2 in the spleen cells of sunitinib treated mice as compared to untreated tumor bearing (TB) mice. We conclude that sunitinib has therapeutic activity, in association with the down regulation of MDSCs and T-regs and has a trend towards the normalization of the inflammatory cytokine levels induced by tumor progression and growth. Based on these results, we suggest that sunitinib reduction of immune suppressive cells is a critical part of its adjuvant immune therapeutic activity.
AB - Mouse mammary tumor virus-Neu (MMTV/neu) transgenic mice on an FVB-background (FVB-neuN) have increased numbers of myeloid derived suppressor cells (MDSCs) and regulatory T-cells (T-regs) in the spleen during mammary tumor induction and progression. Using this transgenic tumor model, we assessed the therapeutic activity of sunitinib, a multi-targeted, tyrosine kinase (TK) inhibitor and its effects on immune-regulatory cells. Our preliminary results show that sunitinib at 40 mg/kg/day, p.o. (per os), delayed the time to tumor induction and reduced the incidence and growth of tumors in FVB-neuN mice. In association with its therapeutic activity, sunitinib reduced the absolute number of splenic T-reg cells (CD4+CD25+CD62L+) and MDSCs (CD11b+Gr1+) that were increased during tumor progression with less activity in mice with gross tumors. A significant decrease in the absolute number of splenic T-regs, dendritic cells (DCs), MDSCs and hematopoietic progenitors (Lin-Sca1+CD90dull) was observed following sunitinib treatment. The frequency of splenic T-regs and hematopoietic progenitors, but not MDSCs was also reduced by sunitinib treatment. Additionally immune-regulatory cytokines and enzymes were down regulated by sunitinib treatment, including TGFβ and NOS2 in the spleen cells of sunitinib treated mice as compared to untreated tumor bearing (TB) mice. We conclude that sunitinib has therapeutic activity, in association with the down regulation of MDSCs and T-regs and has a trend towards the normalization of the inflammatory cytokine levels induced by tumor progression and growth. Based on these results, we suggest that sunitinib reduction of immune suppressive cells is a critical part of its adjuvant immune therapeutic activity.
KW - Her2/neu
KW - MDSC
KW - Sunitinib
KW - T-reg
KW - Tyrosine kinase inhibitor
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U2 - 10.1016/j.intimp.2009.09.023
DO - 10.1016/j.intimp.2009.09.023
M3 - Article
C2 - 19833232
AN - SCOPUS:73149103231
SN - 1567-5769
VL - 10
SP - 140
EP - 145
JO - International Immunopharmacology
JF - International Immunopharmacology
IS - 1
ER -