An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma.
Vaccines based on immune stimulatory complexes (ISCOM) induce T-cell responses against tumor antigen (Ag). However, immune responses are impaired in pancreatic cancer patients. We investigated the efficacy of an ISCOM vaccine in a murine pancreatic carcinoma model. Panc02 cells expressing OVA as a model Ag were induced subcutaneously or orthotopically in the pancreas of C57BL/6 mice. Treatment consisted of an OVA containing ISCOM vaccine, either used alone or in combination with the TLR9 agonist CpG. The ISCOM vaccine effectively induced Ag-specific CTL capable of killing tumor cells. However, in mice with established tumors CTL induction by the vaccine was inefficient and did not affect tumor growth. Lack of efficacy correlated with increased numbers of Treg. Depletion of Treg with anti-CD25 mAb restored CTL induction and prolonged survival. Adding low-dose CpG to the ISCOM vaccine reduced Treg numbers, enhanced CTL responses and induced regression of pancreatic tumors in a CD8(+) T cell-dependent manner. Mice cured from the primary tumor mounted a memory T-cell response against wild-type Panc02 tumors, indicative of epitope spreading. Combining ISCOM vaccines with TLR agonists is a promising strategy for breaking tumor immune evasion and deserves further evaluation for the treatment of pancreatic carcinoma.
Jacobs
Collin
C
Department of Internal Medicine, University Hospitals, University of Munich, Munich, Germany.
Duewell
Peter
P
Heckelsmiller
Klaus
K
Wei
Jiwu
J
Bauernfeind
Franz
F
Ellermeier
Jonathan
J
Kisser
Ulrich
U
Bauer
Christian A
CA
Dauer
Marc
M
Eigler
Andreas
A
Maraskovsky
Eugene
E
Endres
Stefan
S
Schnurr
Max
M
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D057131:Immune Evasion; D007114:Immunization; D007167:Immunotherapy; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D014407:Tumor Cells, Cultured
D000936:Antigen-Antibody Complex; D000951:Antigens, Neoplasm; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D010047:Ovalbumin