An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma

Abstract

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 Pancreatic cancer is one of the most fatal malignancies in the Western world. It is the fourth leading cause of cancer death in the United States. 1 The 5-year survival rate is less than 5% with a median overall survival time of 3-6 months. Despite advancements made over the past two decades in elucidating molecular pathways involved in pancreatic carcinogenesis and in the field of targeted therapy, the clinical outcome has not yet significantly improved. At the time of diagnosis the majority of patients present with locally advanced, unresectable tumors or metastatic disease. Even in the small number of patients who undergo surgery in a curative intention most patients succumb to recurrent and metastatic disease. Therefore, new treatments are urgently needed.Immunotherapy may offer a new treatment option. Pancreatic carcinoma cells can be recognized by T cells, which are found in the blood of pancreatic carcinoma patients.2 Tumor infiltration with T cells represents a positive prognostic factor.3 However, pancreatic carcinomas promote systemic and locally active immunosuppressive mechanisms.4 These include inhibition of T-cell activation, secretion of immunosuppressive cytokines, defects in Ag presentation and recruitment of regulatory T cells (Treg), a subgroup of CD4 þ T cells with suppressor function. 5,6 In patients with pancreatic carcinoma, increased numbers of Treg are found in the

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

“…The murine Panc02 and PancOVA pancreatic cancer cell lines were generated and cultured as described before. 21,45,46 The tumor cell line T110299 was developed from a primary pancreatic tumor of a Ptf1aCre;Kras G12D ;p53 fl/R172H mouse 25 and was kindly provided by Dr. Jens Siveke (Technical University of Munich, Munich, Germany). Fms-like tyrosine kinase 3 ligand (Flt3L)-transduced B16 melanoma cells were kindly provided by Professor Glenn Dranoff (Dana-Farber Cancer Institute, Boston, MA, USA).…”

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

“…Indeed, depletion of Treg with antibodies against CD25 or Folate receptor 4 significantly augmented anti-tumor immune responses in several preclinical mouse models. 29 , [36][37][38] However, as these markers are also expressed on activated CD4 þ FoxP3 -and CD8 þ T-cells such treatments may concomitantly diminish the effector arm of anti-tumor immunity. 28 , 39 This may account for the modest clinical effect and low reproducibility of these depletion strategies.…”

Establishment of an orthotopic pancreatic cancer mouse model: Cells suspended and injected in Matrigel

“…The Pan02 cell lines were established by Corbett et al [22] via injection of 3-methyl-cholanthrene into the pancreas of female C57BL/6 mice. It has been widely used for immunological studies of pancreatic cancer [23][24][25] . The direct injection method, which involves injection of pancreatic cancer cells directly into the mouse pancreas using surgical exposure and ultrasound guidance, is most commonly applied to establish orthotopic xenograft pancreatic carcinoma.…”