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An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma
Author(s) -
Jacobs Collin,
Duewell Peter,
Heckelsmiller Klaus,
Wei Jiwu,
Bauernfeind Franz,
Ellermeier Jonathan,
Kisser Ulrich,
Bauer Christian A.,
Dauer Marc,
Eigler Andreas,
Maraskovsky Eugene,
Endres Stefan,
Schnurr Max
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25399
Subject(s) - ctl* , tlr9 , immune system , immunology , pancreatic cancer , immunotherapy , cancer research , medicine , cancer vaccine , antigen , cd8 , biology , cancer , biochemistry , gene expression , dna methylation , gene
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.