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Carcinoembryonic Antigen-Specific but Not Antiviral CD4⁺ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients¹

Elena Tassi^*,||, Francesca Gavazzi^,#, Luca Albarello^¶, Vladimir Senyukov^*,||, Renato Longhi^**, Paolo Dellabona^,||, Claudio Doglioni^,¶, Marco Braga^,,#, Valerio Di Carlo^,,# and Maria Pia Protti^2,*,||

^* Tumor Immunology Unit, Pancreas Unit, Università Vita-Salute San Raffaele, Experimental Immunology Unit, ^¶ Unità Operativa Anatomia Patologica, ^|| Cancer Immunotherapy and Gene Therapy Program, and ^# Department of Surgery, Scientific Institute H. San Raffaele, Milan, Italy; and ^** Consiglio Nazionale Ricerche-Istituto di Chimica del Riconoscimento Molecolare, Milan, Italy

Pancreatic carcinoma is a very aggressive disease with dismal prognosis. Although evidences for tumor-specific T cell immunity exist, factors related to tumor microenvironment and the presence of immunosuppressive cytokines in patients’ sera have been related to its aggressive behavior. Carcinoembryonic Ag (CEA) is overexpressed in 80–90% of pancreatic carcinomas and contains epitopes recognized by CD4⁺ T cells. The aim of this study was to evaluate the extent of cancer-immune surveillance and immune suppression in pancreatic carcinoma patients by comparing the anti-CEA and antiviral CD4⁺ T cell immunity. CD4⁺ T cells from 23 normal donors and 44 patients undergoing surgical resection were tested for recognition of peptides corresponding to CEA and viral naturally processed promiscuous epitopes by proliferation and cytokine release assays. Anti-CEA CD4⁺ T cell immunity was present in a significantly higher number of normal donors than pancreatic cancer patients. Importantly, whereas CD4⁺ T cells from normal donors produced mainly GM-CSF and IFN-, CD4⁺ T cells from the patients produced mainly IL-5, demonstrating a skew toward a Th2 type. On the contrary, the extent of antiviral CD4⁺ T cell immunity was comparable between the two groups and showed a Th1 type. The immunohistochemical analysis of tumor-infiltrating lymphocytes showed a significantly higher number of GATA-3⁺ compared with T-bet⁺ lymphoid cells, supporting a Th2 skew also at the tumor site. Collectively, these results demonstrate that Th2-immune deviation in pancreatic cancer is not generalized but tumor related and suggests that the skew might be possibly due to factor(s) present at the tumor site.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by: the Cancer Research Institute (preclinical grant), the European Community (Dendritic cells and Novel Immunotherapies), the Italian Ministry of Health, the Italian Ministry of University and Scientific Research, and the Rich Foundation (LDP Pancreas Cancer Research Project).

² Address correspondence and reprint requests to Dr. Maria Pia Protti, Tumor Immunology Unit, Cancer Immunotherapy and Gene Therapy Program, DIBIT, Scientific Institute H. San Raffaele, Via Olgettina 58, 20132 Milan. E-mail address: m.protti{at}hsr.it

³ Abbreviations used in this paper: Tr, T regulatory; CEA, carcinoembryonic Ag; EBNA2, Epstein-Barr nuclear Ag 2; HA, influenza hemagglutinin.