Therapeutic activity of sunitinib for Her2/neu induced mammary cancer in FVB mice.
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 40mg/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(+)CD90(dull)) 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 TGFbeta 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.
Abe
Fuminori
F
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-7660, USA.
Younos
Ibrahim
I
Westphal
Sherry
S
Samson
Holly
H
Scholar
Eric
E
Dafferner
Alicia
A
Hoke
Traci A
TA
Talmadge
James E
JE
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D005260:Female; D057131:Immune Evasion / Q000187:drug effects / Q000235:genetics; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D015703:Antigens, CD; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077210:Sunitinib; C524056:Erbb2 protein, mouse