Immunological Escape Mechanisms in Pancreatic Carcinoma

Abstract

Malignancies have developed several strategies to evade immune surveillance. We have investigated pancreatic cancer cell lines and pancreatic cancer surgical specimens to evaluate possibilities of tumor escape in the Fas system, and local immune suppression. Despite Fas expression the majority of cell lines was resistant to Fas-mediated apoptosis. The Fas-associated phosphatase-1 is a strong candidate to confer Fas resistance in pancreatic cancer cells. In addition, all investigated pancreatic cancer cell lines and cancer specimens expressed Fas ligand. Fas ligand was functional in cancer cell lines as shown by coculture assays of pancreatic cancer cell lines with Jurkat cells as targets. Additional local immune suppression was demonstrated by loss of T-cell receptor/CD3-zeta chain of pancreatic cancer infiltrating T-lymphocytes. We conclude that these tumor escape mechanisms may contribute to the poor prognosis of pancreatic cancer but also represent targets for new treatment modalities.

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

“…However, mechanisms of immune evasion adopted by the tumor (11)(12)(13)(14)(15) as well as released factors and immune regulatory cells present at the tumor site possibly affect the efficacy of antitumor immunity in pancreatic cancer (16 -20). The adaptive immune response mediated by effector CD4 ϩ Th cells is highly heterogeneous and based on the development of distinct subsets characterized by different cytokine production.…”

An Overview on Immunotherapy of Pancreatic Cancer

“…Two recently discovered B7-family members, B7-H1 (also known as PD-L1) and B7-DC (also known as PD-L2) also seem to interact with T-cell costimulatory and counter-regulatory inhibitory receptors 18,29,30 . PD-L1, which is upregulated on T cells when they become activated, seems to control a counter-regulatory immunological checkpoint when it binds PD-1 26,28,29.…”

“…For example, T-cell recognition of pancreatic tumours might be inhibited or suppressed due to the downregulation of human leukocyte antigen (HLA) CLASS I tumour-antigen complexes on tumour cells by a range of intracellular mechanisms 4, 7 -upregulation of immuneinhibition molecules 11,12,13,14,15,16,17 , loss of immune-regulation signals 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30 , defects in immune-cell tumour localization 31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51 and loss of co-stimulatory molecules 52,53,54,55,56,…”

Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: Implications for anti-tumor immune response

“…In addition, pancreatic cancer patients often exhibit poor anti-tumor immune responses either locally or systemically. 1 Several mechanisms have been suggested whereby pancreatic carcinoma may escape immune surveillance, 2 including immune suppression by soluble inhibitory factors such as interleukin (IL)-10 and transforming growth factor (TGF)-β 3 and Fas Ligand (FasL)-mediated killing of Fas-expressing immune effector cells. 4,5 Recently, we observed that pancreatic carcinoma cell lines, in addition to anti-inflammatory growth factors such as IL-10 and TGF-β, express a wide array of pro-inflammatory cytokines, including IL-18.…”