Increase in frequency of myeloid‐derived suppressor cells in mice with spontaneous pancreatic carcinoma

Pancreatic adenocarcinoma is one of the deadliest cancers with poor survival and limited treatment options. Immunotherapy is an attractive option for this cancer that needs to be further developed. Tumours have evolved a variety of mechanisms to suppress host immune responses. Understanding these responses is central in developing immunotherapy protocols. The aim of this study was to investigate potential immune suppressor mechanisms that might occur during development of pancreatic tumours. Myeloid‐derived suppressor cells (MDSC) from mice with spontaneous pancreatic tumours, mice with premalignant lesions as well as wild‐type mice were analysed. An increase in the frequency of MDSC early in tumour development was detected in lymph nodes, blood and pancreas of mice with premalignant lesions and increased further upon tumour progression. The MDSC from mice with pancreatic tumours have arginase activity and suppress T‐cell responses, which represent the hallmark functions of these cells. Our study suggests that immune suppressor mechanisms generated by tumours exist as early as premalignant lesions and increase with tumour progression. These results highlight the importance of blocking these suppressor mechanisms early in the disease in developing immunotherapy protocols.

[1]  T. Skaar,et al.  Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition1 , 2009, The Journal of Immunology.

[2]  Michelle Collazo,et al.  Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice1 , 2008, The Journal of Immunology.

[3]  W. Nacken,et al.  Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein , 2008, The Journal of experimental medicine.

[4]  T. Skaar,et al.  MUC1 Enhances Tumor Progression and Contributes Toward Immunosuppression in a Mouse Model of Spontaneous Pancreatic Adenocarcinoma1 , 2008, The Journal of Immunology.

[5]  V. Bronte,et al.  Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells , 2008, Immunological reviews.

[6]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[7]  P. De Baetselier,et al.  Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. , 2008, Blood.

[8]  D. Tuveson,et al.  Dynamics of the immune reaction to pancreatic cancer from inception to invasion. , 2007, Cancer research.

[9]  M. Smyth,et al.  Immune surveillance of tumors. , 2007, The Journal of clinical investigation.

[10]  G. Rabinovich,et al.  Immunosuppressive strategies that are mediated by tumor cells. , 2007, Annual review of immunology.

[11]  Paolo Serafini,et al.  Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. , 2006, The Journal of clinical investigation.

[12]  Paolo Serafini,et al.  Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. , 2006, Seminars in cancer biology.

[13]  M. Manns,et al.  Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses. , 2006, Cancer research.

[14]  E. Furth,et al.  Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. , 2006, Cancer research.

[15]  E. Jaffee,et al.  Immunotherapy for pancreatic cancer — science driving clinical progress , 2005, Nature Reviews Cancer.

[16]  P. Sinha,et al.  Reduction of Myeloid-Derived Suppressor Cells and Induction of M1 Macrophages Facilitate the Rejection of Established Metastatic Disease1 , 2005, The Journal of Immunology.

[17]  J. Biggs,et al.  A Spontaneously Arising Pancreatic Tumor Does Not Promote the Differentiation of Naive CD8+ T Lymphocytes into Effector CTL1 , 2004, The Journal of Immunology.

[18]  S. Ostrand-Rosenberg,et al.  Animal models of tumor immunity, immunotherapy and cancer vaccines. , 2004, Current opinion in immunology.

[19]  M. Colombo,et al.  Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. , 2003, Blood.

[20]  T. Greten,et al.  Stat3 and NF-κB activation prevents apoptosis in pancreatic carcinogenesis ☆ ☆☆ , 2002 .

[21]  T. Greten,et al.  Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. , 2002, Gastroenterology.

[22]  T. Mattfeldt,et al.  A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. , 2001, Genes & development.

[23]  R. Schmid,et al.  Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice. , 1998, Gastroenterology.