Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model.
The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, B7-H1 and B7-DC, has been suggested to play an important role in tumor evasion from host immunity. Pancreas cancer patients with B7-H1 expression have a poor prognosis. B7-H1 blocking has been shown to inhibit the development of a subcutaneous tumor from a pancreas cancer cell line. In this study, we investigated the effects of B7-DC as well as B7-H1 blockade in vivo in a murine pancreatic cancer model. Pancreatic cancer cells (Panc02) were inoculated in the pancreas of C57BL/6 mice. Five weeks later, tumor sizes were measured and the mice bearing appropriate size of tumors received the following treatments. Blocking antibodies against B7-H1 or B7-DC (200 microg) were administered 3 times/week for 3 weeks. Cells infiltrating the tumors were characterized by immunohistochemistry. Effects of antibodies on cytokine and FoxP3 expression were examined by quantitative RT-PCR. In vitro cultured Panc02 cells expressed B7-H1 upon IFN-gamma stimulation. However, expression of B7-H1 and B7-DC was found mainly on CD45-positive infiltrating cells and rarely on cancer cells in vivo. Treatment with both antibodies significantly decreased tumor growth in vivo. B7-DC blockade decreased the levels of IL-10 and FoxP3, suggesting that regulatory systems are mainly inhibited at the tumor site. B7-H1 blockade increased the levels of IFN-gamma and FoxP3. Collectively, blocking of B7-H1 or B7-DC efficiently induced regression of pre-established pancreatic cancers by up-regulating IFN-gamma production and down-regulating IL-10 production at the tumor site.
Okudaira
Keisuke
K
Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
Hokari
Ryota
R
Tsuzuki
Yoshikazu
Y
Okada
Yoshikiyo
Y
Komoto
Shunsuke
S
Watanabe
Chikako
C
Kurihara
Chie
C
Kawaguchi
Atsushi
A
Nagao
Shigeaki
S
Azuma
Miyuki
M
Yagita
Hideo
H
Miura
Soichiro
S
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000187:drug effects* / Q000276:immunology; D060890:B7-H1 Antigen; D039481:CD11b Antigen / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000032:analysis; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects*; D000097382:CD68 Molecule
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D039481:CD11b Antigen; D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D016753:Interleukin-10; D017493:Leukocyte Common Antigens; D008562:Membrane Glycoproteins; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C498919:Cd274 protein, mouse; C498833:Foxp3 protein, mouse; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; C516770:Ptprc protein, mouse