Dataset Information

The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC).

ABSTRACT: Recently, increasing evidence has indicated that the presence of tumor infiltrating immune cells has shown predictive significance for many solid tumors. Present study was performed to evaluate the predictive value of stromal tumor-infiltrating lymphocytes (TILs) for the presence of liver metastasis and overall survival in PDAC (pancreatic ductal adenocarcinoma) patients after complete resection and to explore the potential role of lymphocytes in PDAC. A total of 155 resectable patients with PDAC were enrolled in our study. Stromal TIL density was investigated in hematoxylin and eosin-stained sections of surgical specimens and scored. The effect and possible mechanism of lymphocytes on cancer cells was evaluated using co-culture techniques and ELISA test. Stromal TIL negative status (HR = 2.80, 95% CI 1.75-4.48, P < 0.01) was not only an independent predictor of worse OS (HR = 2.7, 95% CI 1.80-4.06, P = <0.01) but also a significant independent predictor of liver metastasis. Higher CEA (P = 0.01) or CA19-9 (P = 0.01) levels were associated with low stromal TIL density. Stromal TIL negative patients appeared to develop tumors with a higher CEA (P = 0.01), larger diameter (P = 0.05) and advanced stage (P = 0.02). The co-culture experiment suggests that lymphocytes can inhibit pancreatic cancer cell proliferation. Further ELISA and cell culture test indicate that lymphocytes may cause pancreatic cancer cells apoptosis through TNF-alpha secretion. Our data suggest a potential favorable role of stromal TILs in predicting liver metastasis and overall survival of patients with PDAC after complete resection. Lymphocytes may inhibit the growth of PDAC through TNF-alpha secretion, which suggest a potential therapeutic approach against PDAC.

SUBMITTER: Lianyuan T

PROVIDER: S-EPMC5902243 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC).

Lianyuan Tao T Dianrong Xiu X Chunhui Yuan Y Zhaolai Ma M Bin Jiang J

Cancer biology & therapy 20180222 4

Recently, increasing evidence has indicated that the presence of tumor infiltrating immune cells has shown predictive significance for many solid tumors. Present study was performed to evaluate the predictive value of stromal tumor-infiltrating lymphocytes (TILs) for the presence of liver metastasis and overall survival in PDAC (pancreatic ductal adenocarcinoma) patients after complete resection and to explore the potential role of lymphocytes in PDAC. A total of 155 resectable patients with PDA ...[more]

PMID: 29313457

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Project description:BackgroundTumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture.MethodsPatients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety.Results17 patients underwent TIL harvest and 16 were treated on protocol (NCT03610490), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers.ConclusionsTIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.

Project description:BackgroundOne of the deadliest and most prevalent cancer is pancreatic ductal adenocarcinoma (PDAC). Microarray has become an important tool in the research of PDAC genes and target therapeutic drugs.ObjectivesThis study intends to clarify the promising prognostic and biomarker targets in PDAC using GSE78229 and GSE62452 datasets, publicly accessible at the Gene Expression Omnibus database.Materials and methodsUtilizing GEOquery, Bio base, gplots, and ggplot2 packages in the R program, this study detects 428 differentially expressed genes that are further applied to build a co-expression network by the weighted correlation network analysis (WGCNA). The turquoise module presented a higher correlation with PDAC progression. 79 candidate genes were selected based on the co-expression and protein-protein interaction (PPI) networks. In addition, the functional enrichment analysis was studied.ResultsFive significant KEGG pathways linked to PDAC were detected, in which the endoplasmic reticulum protein processing pathway was remarked to be vital. The resulting 19 hub genes as HSPA4, PABPC1, HSP90B1, PPP1CC, USP9X, EIF2S3, MSN, RAB10, BMPR2, P4HB, UBC, B2M, SLC25A5, MMP7, SPTBN1, RALB, DNAJB1, CENPE, and PDIA6 were identified by the Network Analyst web tool founded on PPI network by the STRING. These were identified as the most connected hub proteins. The quantification of the expression of levels and survival probabilities were analyzed overall survival (OS) of the real hub genes and were investigated by Kaplan-Meier (KM) plotter through The Cancer Genome Atlas Program (TCGA) database.ConclusionsThe protein-protein interactions and KEGG pathway enrichment by DAVID indicated that some pathways were involved in PDAC, such as "pathways in cancer (hsa05200)", "protein processing in the endoplasmic reticulum (hsa04141)", "antigen processing and presentation (hsa04612)", "dopaminergic synapse (hsa04728)", and "measles (hsa05162)"; in which these pathways, the "protein processing in endoplasmic reticulum (hsa04141)", was further studied because of its closely relationship with PDAC. The rest of the hub genes reviewed throughout the study might be promising targets for diagnosing and treating PDAC and relevant diseases.

Project description:Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

Dataset Information

The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC).

Publications

The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC).

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