Specific immune recognition of pancreatic carcinoma by patient-derived CD4 and CD8 T cells and its improvement by interferon-γ

Schmitz-Winnenthal, Friedrich H.; Escobedo, Laura V.; Beckhove, Philipp; Schirrmacher, Volker; Bucur, Mariana; Ziouta, Yvonne; Volk, Christine; Schmied, Bruno M.; Koch, M.; Antolovic, Dalibor; Weitz, Jürgen; Büchler, M. W.; Z’graggen, Kaspar

doi:10.3892/ijo.28.6.1419

Cited by 21 publications

(26 citation statements)

References 25 publications

(29 reference statements)

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“…Animal experiments showed that CIITA-transfected tumor cells were rejected via activation of the host immune response (22,23). In vitro experiments with human tumor cells also showed enhanced immunogenictiy on (IFNg-induced) expression of CIITA (29,30). In agreement with this, we and others have shown that high amounts of tumor infiltrating lymphocytes correlate with a better prognosis in (colo)rectal cancer patients (3, 4, 6).…”

Section: Discussionsupporting

confidence: 75%

Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients

Bruin

Velde

Krieken

et al. 2008

Clinical Cancer Research

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Purpose: The development of local and distant recurrences is a major problem in the treatment of rectal cancer patients. In this study, we investigated whether epithelial human leukocyte antigen-DR (HLA-DR) expression allowed discrimination between high and low tumor recurrence rates, and analyzed the mechanism behind its expression. Experimental Design: The role of IFNg in HLA-DR expression was studied in rectal cancer cell lines and tumors by promoter-specific analyses of class II transactivator (CIITA). The predictive value of epithelial HLA-DR expression was investigated by immunohistochemical evaluation of 1,016 rectal tumors, obtained from a large prospective trial. Associations with recurrences and survival were determined by univariate and multivariate log-rank testing. Results: HLA-DR was induced by IFNg in rectal cancer cell lines. Activity of the IFNg-inducible pIV-CIITA promoter correlated with epithelial HLA-DR expression in rectal tumors. Patients with HLA-DR^positive tumors developed less frequent local and distant recurrences [1.6% versus 9.1% (P = 0.0015) and 15.3% versus 29.9% (P < 0.0001), respectively, after 5 years of followup] and had better survival (78.6% versus 61.3%; P < 0.0001) than patients with HLA-DRn egative tumors. Epithelial HLA-DR was more often found in lower tumor-node-metastasis (TNM) stages. Next to TNM and circumferential resection margin, HLA-DR expression was independently associated with lower distant recurrence rates and prolonged survival. Conclusions: Epithelial HLA-DR expression can be used as a marker to discriminate patients with high or low risk of developing recurrences.The possible involvement of IFNg, the relationship with lowerTNM stages, and the independent effect on recurrence development together suggest that the host immune response plays an important role in controlling tumor cells.In the treatment of rectal cancer patients, local and distant recurrences are a major problem because these are associated with both high mortality and morbidity. The introduction of total mesorectal excision (TME) surgery in combination with preoperative radiotherapy has been shown to be useful in reducing local recurrences. However, more than 25% of the patients develop metastases within 5 years after surgical treatment with curative intent (1, 2).We and others have shown that (colo)rectal cancer patients develop less frequent recurrences when high numbers of infiltrating immune cells are present in the tumor (3 -6). An optimal antitumor immune response usually requires activation of CD4 + and CD8 + T lymphocytes with a tumor-associated antigen. CD8 + T cells are activated by antigen presented by human leukocyte antigen (HLA) class I molecules whereas CD4 + T cells are activated by antigen presented by HLA class II molecules, normally expressed on professional antigen-presenting cells such as dendritic cells and macrophages. We have recently shown that a subgroup of tumors expressed high levels of HLA classes I and II and several other immune-related genes. Important...

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Section: Discussionsupporting

confidence: 75%

Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients

Bruin

Velde

Krieken

et al. 2008

Clinical Cancer Research

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“…MHC class I expression by tumor cells is essential for their recognition by CD8 cytolytic T cells. Down-regulation of MHC class I is a common tumor escape mechanism (34); therefore, we investigated whether prostate tumors in our model systems expressed MHC class I. IFN-g produced at the tumor site is important in stimulating the expression of MHC classes I and II molecules by malignant cells, facilitating their clearance (35). We confirmed that this concept is important in our models by demonstrating the induction of MHC class I expression on TRAMP-C2 cells cultured in the presence of IFN-g. Crucially, vaccination of C57BL/6 mice challenged with TRAMP-C2 tumor cells induced increased expression of IFN-g in tumors that was associated with increased MHC class I expression in vivo.…”

Section: Discussionmentioning

confidence: 99%

Prostate Stem Cell Antigen Vaccination Induces a Long-term Protective Immune Response against Prostate Cancer in the Absence of Autoimmunity

et al. 2008

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Prostate stem cell antigen (PSCA) is an attractive antigen to target using therapeutic vaccines because of its overexpression in prostate cancer, especially in metastatic tissues, and its limited expression in other organs. Our studies offer the first evidence that a PSCA-based vaccine can induce long-term protection against prostate cancer development in prostate cancer-prone transgenic adenocarcinoma mouse prostate (TRAMP) mice. Eight-week-old TRAMP mice displaying prostate intraepithelial neoplasia were vaccinated with a heterologous prime/boost strategy consisting of gene gun-delivered PSCA-cDNA followed by Venezuelan equine encephalitis virus replicons encoding PSCA. Our results show the induction of an immune response against a newly defined PSCA epitope that is mediated primarily by CD8 T cells.

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“…Key findings include the fact that PDAC cells are specifically recognized by autologous T lymphocytes [9] and that chemokines or their receptors, such as CXCL14 or CXCL16 and its corresponding receptor CXCR6, are found in PDAC that could mediate interactions with inflammatory cells in particular [10][11][12][13]. Moreover, major histocompatibility antigen (MHC) class I and class II are found on a variety of tumor cells, including pancreatic adenocarcinoma cells [14], and it has been assumed that they provide the immunologic recognition structure of the tumor by presenting either an "altered self" or a "non-self antigen" to T lymphocytes [15,16].…”

Section: Introductionmentioning

confidence: 99%

MHC class II expression in pancreatic tumors: a link to intratumoral inflammation

et al. 2011

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Major histocompatibility complex class II antigens (MHC class II) are constitutively expressed by professional antigen presenting cells and present antigenic peptides to specific CD4+ T lymphocytes. MHC class II expression, however, can also be induced on epithelial cells and in a variety of solid tumors. We tested MHC class II expression on tissue samples derived from patients with pancreatic ductal adenocarcinoma (PDAC) and pancreatic endocrine tumors (PET). Immunohistochemistry revealed MHC class II expression in 86 of 112 (76.8%) PDAC samples and in 30 of 43 (70.0%) PET samples. In PDAC and PET, MHC class II expression correlated significantly with severity and activity of intratumoral inflammation, as well as with the infiltration of CD4+ T lymphocytes. High MHC class II expression significantly correlated with a better histological grade of differentiation in PDAC. In vitro MHC class II expression could be induced on PDAC tumor cell lines by interferon-γ. These cells were then able to present the staphylococci enterotoxin B superantigen to T lymphocytes, which resulted in T cell proliferation. Our findings suggest that MHC class II expression on pancreatic tumor cells is induced by the intratumoral inflammatory reaction in pancreatic tumors.

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Specific immune recognition of pancreatic carcinoma by patient-derived CD4 and CD8 T cells and its improvement by interferon-γ

Cited by 21 publications

References 25 publications

Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients

Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients

Prostate Stem Cell Antigen Vaccination Induces a Long-term Protective Immune Response against Prostate Cancer in the Absence of Autoimmunity

MHC class II expression in pancreatic tumors: a link to intratumoral inflammation

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