Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.
Drug Discovery ; Humans ; Lung Neoplasms ; drug therapy ; immunology ; metabolism ; Membrane Proteins ; metabolism ; Pancreatic Neoplasms ; drug therapy ; immunology ; metabolism ; Signal Transduction ; drug effects ; physiology ; T-Lymphocytes, Regulatory ; metabolism ; Transforming Growth Factor beta ; antagonists & inhibitors ; immunology ; metabolism

This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100-200 mg/m) and cyclophosphamide (15-35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR T cell 2.1 × 10/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5-8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.
Aged ; Biliary Tract Neoplasms ; immunology ; therapy ; Female ; Humans ; Immunotherapy, Adoptive ; Male ; Middle Aged ; Pancreatic Neoplasms ; immunology ; therapy ; Receptor, ErbB-2 ; immunology ; Receptors, Chimeric Antigen ; immunology ; T-Lymphocytes ; immunology

Autoimmune Diseases ; diagnostic imaging ; immunology ; Female ; Humans ; Immunoglobulin G ; immunology ; Middle Aged ; Pancreatic Neoplasms ; diagnostic imaging ; immunology ; Pancreatitis ; diagnostic imaging ; immunology ; Tomography, X-Ray Computed

Antineoplastic Agents, Immunological ; immunology ; pharmacology ; Cell Line, Tumor ; GPI-Linked Proteins ; antagonists & inhibitors ; immunology ; Humans ; Neoplasm Proteins ; analysis ; immunology ; Pancreatic Neoplasms ; drug therapy ; immunology ; pathology

While the main product of Jeju Island is citrus fruit and the prevalence of atopic dermatitis among the students who live there is relatively high, the incidence of pancreatic cancer is lowest in Korea. Systematic reviews reporting allergic history and intake of citrus fruit as protective factors against pancreatic cancer (PCC) were published in 2005 and 2008, respectively. Although there were discrepancies in the results of the subgroup analyses between case-control and cohort studies, it is necessary to evaluate an interaction effect between allergic history and intake of citrus fruits on PCC risk.
Allergy and Immunology ; Case-Control Studies ; Citrus* ; Cohort Studies ; Dermatitis, Atopic ; Humans ; Incidence ; Korea ; Observational Study* ; Pancreatic Neoplasms* ; Prevalence ; Risk Factors

PURPOSE: Vaccine strategies utilizing dendritic cells (DCs) to elicit anti-tumor immunity are the subject of intense research. Although we have shown that DCs pulsed with heat-treated tumor lysate (HTL) induced more potent anti-tumor immunity than DCs pulsed with conventional tumor lysate (TL), the underlying molecular mechanism is unclear. In order to explore the molecular basis of this approach and to identify potential antigenic peptides from pancreatic cancer, we analyzed and compared the major histocompatibility complex (MHC) ligands derived from TL- and HTL-pulsed dendritic cells by mass spectrophotometry. MATERIALS AND METHODS: Human monocyte-derived dendritic cells were pulsed with TL or HTL prior to maturation induction. To delineate differences of MHC-bound peptide repertoire eluted from DCs pulsed with TL or HTL, nanoflow liquid chromatography-electrospray ionization-tandem mass spectrometry (nLC-ESI-MS-MS) was employed. RESULTS: HTL, but not TL, significantly induced DC function, assessed by phenotypic maturation, allostimulation capacity and IFN-gamma secretion by stimulated allogeneic T cells. DCs pulsed with TL or HTL displayed pancreas or pancreatic cancer-related peptides in context of MHC class I and II molecules. Some of the identified peptides had not been previously reported as expressed in pancreatic cancer or cancer of other tissue types. CONCLUSION: Our partial lists of MHC-associated peptides revealed the differences between peptide profiles eluted from HTL-and TL-loaded DCs, implying that induced heat shock proteins in HTL chaperone tumor-derived peptides enhanced their delivery to DCs and promoted cross-presentation by DC. These findings may aid in identifying novel tumor antigens or biomarkers and in designing future vaccination strategies.
Antigens, Neoplasm/*immunology ; Cell Line, Tumor ; Dendritic Cells/*immunology ; Humans ; Pancreatic Neoplasms/*immunology

OBJECTIVETo investigate retrospectively the relationship between clinicopathological factors and lymph node matastasis of pancreatic adenocarcinoma.

METHODSThe clinicopathological factors, including gender, age, preoperative CA-19-9 level etc. of 71 patients with pancreatic adenocarcinoma were summarized to analyze the relationship between those factors and lymph node matastasis.

RESULTSAmong the 71 cases, there were 49 males (69.0%) and 22 females (31.0%). Forty-eight were ≥ 60 (67.6%) and 23 were < 60 (32.4%) years old. Twenty patients had normal preoperative CA-19-9 level (28.2%) and 51 had elevated level (71.8%). The tumor in 43 (60.6%) cases located in the pancreatic head and neck, and 28 (39.4%) in the body and tail. The tumors in 8 patients were well-differentiated (11.3%), 27 were moderately differentiated (38.0%), and 36 were poorly differentiated (50.7%). The maximum diameter of the tumor was ≤ 2 cm in 11 cases (15.5%), 2 - 5 cm in 45 cases (63.4%), and > 5 cm in 15 cases (21.1%). Ten patients had tumor confined to the pancreas (14.1%), and 61 invaded peripancreatic tissues (85.9%). Vascular tumor thrombus was found in 48 cases (67.6%), and 23 cases were absent (32.4%). Thirty-six cases had lymph node matastasis (50.7%). Univariate chi-square test revealed that differentiation and range of local infiltration were significantly associated with lymph node meatstasis (P < 0.05). Multivariate logistic regression analysis also showed that differentiation and range of local infiltration were significantly associated with lymph node meatstasis (P < 0.05).

CONCLUSIONSThe differentiation of tumor and range of local infiltration of pancreatic adenocarcinoma are significantly associated with lymph node metastasis. There is no significant relationship of location of the tumor, maximum diameter, presence or absence of vascular tumor thrombus with lymph node metastasis. Therefore, special attention should be paid to lymph node dissection in cases with a poorly differentiated pancreatic adenocarcinoma invading into peripancreatic tissues.

Adenocarcinoma ; immunology ; pathology ; surgery ; Adult ; Aged ; Aged, 80 and over ; CA-19-9 Antigen ; metabolism ; Female ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplastic Cells, Circulating ; Pancreatectomy ; Pancreatic Neoplasms ; immunology ; pathology ; surgery ; Retrospective Studies ; Tumor Burden

OBJECTIVETo investigate clinicopathological features of fibrous mass-forming chronic pancreatitis (FMCP), to compare clinicopathological and immunohistochemical characteristics between autoimmune pancreatitis (AIP) and fibrous mass-forming non-autoimmune pancreatitis (nAIP) and to provide evidence for pathological diagnosis, differential diagnosis and clinical treatment strategy.

METHODSClinicopathological features were analyzed in 81 cases of FMCP. Infiltrating IgG4(+) plasmacytes were counted by immunohistochemical staining.

RESULTSAmong 81 cases of FMCP, 20 cases were diagnosed as AIP and 61 cases were interpreted as nAIP. AIP was more common in males over 50 years, whereas nAIP was seen in much younger patients (P = 0.001). The amount of inflammatory cells in the stroma of AIPs was remarkable higher than that in nAIPs (P = 0.002). The incidence of neuritis in AIPs (100%, 20/20) was also higher compared with that of nAIPs (75.4%, 46/61; P = 0.017). Storiformed-fibrosis was more common in AIPs (95.0%, 19/20) than in nAIPs (1.6%, 1/61;P = 0.000). Pancreatic intraepithelial neoplasia (PanIN) was observed in 50.0%(10/20) of AIPs and 32.8%(20/61) of nAIPs, with a greater severity observed in AIPs (P = 0.031). Tubular complex (TC) was more commonly observed in AIPs (65.0%, 13/20) than nAIPs (26.2%, 16/61;P = 0.002). Among 81 cases of FMCP, 61 cases had less than 11 IgG4(+) plasmacytes /HPF, 7 cases had 10-30/HPF and 13 cases had over 30/HPF.

CONCLUSIONSFMCPs include both AIP and nAIP. AIP has distinct pathological features and the presence of IgG4(+) plasmacyte is an important diagnostic parameter. FMCP appears to be an important precancerous lesion of pancreatic ductal adenocarcinoma. Surgery may be considered for patients with FMCP due to its mass-forming nature. In contrast, patients with AIP are treated medically due to its steroid-responsiveness. Therefore, accurate and timely diagnosis of AIP is of clinical relevance to avoid unnecessary surgical complications and to prevent progression of the disease.

Adult ; Aged ; Autoimmune Diseases ; immunology ; pathology ; surgery ; Carcinoma, Pancreatic Ductal ; immunology ; pathology ; surgery ; Diagnosis, Differential ; Female ; Fibrosis ; Humans ; Immunoglobulin G ; metabolism ; Male ; Middle Aged ; Pancreas ; pathology ; Pancreatic Neoplasms ; immunology ; pathology ; surgery ; Pancreatitis, Chronic ; immunology ; pathology ; surgery ; Plasma Cells ; immunology ; Precancerous Conditions ; immunology ; pathology ; surgery ; Young Adult

Extraosseous Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is an uncommon, aggressive, and malignant tumor with a poor patient outcome. Its occurrence in the lesser sac is a rare event and to the best of our knowledge, has not been previously described. The present case was clinically and radiologically misdiagnosed as a pancreatic tumor/gastrointestinal stromal tumor. Histopathology revealed a tumor with "small round cells" that were positive for CD99, confirming the diagnosis of ES/PNET. This report highlights the importance of considering Ewing's sarcoma in the differential diagnosis of intraabdominal, extraintestinal masses.
Antigens, CD/analysis ; Biopsy ; Cell Adhesion Molecules/analysis ; *Diagnostic Errors ; Female ; Humans ; Immunohistochemistry ; Middle Aged ; Neuroectodermal Tumors, Primitive, Peripheral/*diagnosis/immunology/pathology/therapy ; Pancreatic Neoplasms/*diagnosis ; Peritoneal Neoplasms/*diagnosis/immunology/pathology/therapy ; Predictive Value of Tests ; Sarcoma, Ewing/*diagnosis/immunology/pathology/therapy ; Tomography, X-Ray Computed ; Tumor Markers, Biological/analysis

OBJECTIVETo validate those obtained immunogenic membrane antigens candidate of human pancreatic cancer in the performed research.

METHODSIn the pre-studies, serum IgG purified from clinically collected sera of pancreatic cancer patients underwent immunoblot with human pancreatic cancer cell line SW1990 membrane protein, totally obtained 9 positive protein spots. Number 5 and 6 positive dots of immunoblot were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and peptide mass fingerprinting matching. The candidate membrane antigens were further validated in cell lines by RT-PCR and real-time PCR. RNA of human normal pancreatic tissue and pancreatic cancer tissue was extracted respectively, different gene expression level of prohibitin 2 was studied by real-time PCR.

RESULTSNumber 5 and 6 positive dots were identified as prohibitin 2 and prohibitin. RT-PCR and real-time PCR all showed that gene of prohibitin 2 and prohibitin were expressed in the human pancreatic cancer cell line SW1990, AsPc and P3 respectively, especially in P3 cell with highest expression (t = 7.442, P < 0.01). In addition, gene expression level of prohibitin 2 was significant higher in human pancreatic cancer than that of normal pancreatic tissue (t = 0.893, P < 0.01).

CONCLUSIONSProhibitin 2 and prohibitin are both differently expressed in the pancreatic cancer cell line SW1990, AsPc and P3. Prohibitin 2 is obvious highly expressed in human pancreatic cancer tissue. Prohibitin 2 and prohibitin might be the candidate immunogenic membrane antigens of human pancreatic cancer.

Antigens, Neoplasm ; genetics ; metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Membrane Proteins ; genetics ; metabolism ; Pancreatic Neoplasms ; genetics ; immunology ; metabolism ; Proteomics ; methods ; Repressor Proteins ; genetics ; metabolism