Prognostic value of <i>PDL1</i> expression in pancreatic cancer

Birnbaum, David; Finetti, Pascal; Lopresti, Alexia; Gilabert, Marine; Poizat, Flora; Turrini, Olivıer; Raoul, Jean‐Luc; Delpero, Jean‐Robert; Moutardier, Vincent; Birnbaum, Daniel; Mamessier, Émilie; Bertucci, François

doi:10.18632/oncotarget.11685

Cited by 81 publications

(65 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has already been reported in several cancers, 15,58,[62][63][64][65][66] although a favorable prognostic value has been reported in other cancers. 50,55,59,[67][68][69] For comparison and to our knowledge, only four studies-three publications 8,15,42 and one meeting presentation 70 -have described PDL1 expression and clinicopathological correlations in STS.…”

Section: Discussionmentioning

confidence: 63%

“…In these cases, PDL1 was upregulated likely because of a negative feedback loop that follows cytotoxic cells activation, notably through the production of IFNg, a known regulator of PDL1 expression. In contrast, PDL1 expression was unfavorable in pancreatic carcinoma, 66 where expression was associated with a less strong cytotoxic profile than in breast cancer and GISTs and with several signs of T-cell exhaustion, with enrichment in inhibitory molecules and pro-tumor populations (Tregs, myeloid-derived suppressor cells), and downregulation of most MHC class-I members suggesting a defect in antigen presentation. In the present study, the PDL1-high signature suggested a strong cytotoxic T-cell response, without defect in antigen presentation or enrichment in inhibitory molecules and pro-tumor populations, but with some degree of T-cell exhaustion and negative regulation of Tcell response.…”

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

et al. 2017

Self Cite

View full text Add to dashboard Cite

Soft-tissue sarcomas (STS) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. In the quest for new treatments, the immune system represents an attractive therapeutic target. Recently, PD1/PDL1 inhibitors showed very promising results in patients with solid tumors. PDL1 expression has been rarely studied in STS, in small series only, by using immunohistochemistry (IHC), and with non-concordant prognostic implications. Here, we have analyzed PDL1 mRNA expression in 758 clinical STS samples retrospectively profiled using DNA microarrays and RNAseq, and searched for correlations with clinicopathological variables including metastasis-free survival (MFS) after surgery. PDL1 expression was heterogeneous across the samples. PDL1-high samples (41%) were more frequently leiomyosarcomas and liposarcomas, and showed more frequently a complex genetic profile and a high-risk CINSARC signature. No correlation existed with other clinicopathological features such as tumor site, depth, and pathological tumor grade and size. In multivariate prognostic analysis, the PDL1-high class was associated with shorter MFS, independently of the pathological type and the CINSARC signature. Analysis of correlations with biological factors suggested the existence in tumors of the PDL1-high class of a strong and efficient cytotoxic T-cell response, however associated with some degree of T-cell exhaustion and negative regulation. In conclusion, we show that PDL1 expression refines the prediction of metastatic relapse in operated localized STS, and that PD1/PDL1 blockade holds potential to improve patient survival by reactivating inhibited T cells to increase the antitumor immune in PDL1-high tumors.

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 93%

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…PD-L1 expression by tumor cells has been associated with a poorer prognosis or advanced disease (20, 34–36). About 80% of PC cases express PD-L1, of which 20% have up-regulated expression of PD-L1 (compared to normal pancreatic tissue) and tend to be highly invasive and recurrent (37, 38). …”

Section: Resultsmentioning

confidence: 99%

Ex Vivo PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA-Specific T Cells in Pancreatic Cancer Patients

Yuan

Xue

Behboudi

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer (PC). In this study, we have characterised the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2 restricted peptide, pCEA691–699, isolated from the peripheral T cell repertoire of PC patients and sought to determine if ex vivo PD-L1 & TIM3 blockade could enhance CTL function. CD8+ T cell lines were generated from peripheral blood mononuclear cells (PBMCs) of 18 HLA-A2+ patients with PC and from 15 healthy controls. In vitro peptide specific responses were evaluated by flow cytometry after staining for intracellular cytokine production and CSFE cytotoxicity assays using pancreatic cancer cell lines as targets. Cytokine secreting functional CEA691-specific CTL lines were successfully generated from 10 of 18PC patients, with two CTL lines able to recognise and kill both CEA691 peptide-loaded T2 cells and CEA+ HLA-A2+ pancreatic cancer cell lines. In the presence of ex vivo PD-L1 blockade, functional CEA691-specific CD8+ T cell responses, including IFN-γ secretion and proliferation, were enhanced and this effect was more pronounced on Ag-specific T cells isolated from tumor draining lymph nodes. These data demonstrate that CEA691-specific CTL can be readily expanded from the self-restricted T cell repertoire of PC patients and that their function can be enhanced by PD-L1 blockade.

show abstract

“…CTLA4 and PD-1 pathways are the two negative co-stimulatory pathways mediating immunosuppression in a diversity of cancer types, including melanoma, ovarian and lung cancers(41). In pancreatic cancer, over-expression of PDL-1 results in lymphocyte exhaustion, down-regulation of most MHC class I members, and is associated with shorter disease-free survival and overall survival(42). Moreover, PAAD is a heterogeneous disease involving types of molecular and cellular pathways.…”

Section: Discussionmentioning

confidence: 99%

Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics

Yan

Gao

Trinh

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Pancreatic adenocarcinomas (PAAD) often are not diagnosed until their late stages leaving no effective treatments. Currently immunotherapy provides a promising treatment option against this malignancy. However, a set of immunotherapy agents benefit patients with many types of cancer, but not PAAD. Sharing the origin in the same organ, diabetes and PAAD tend to occur concurrently. We aimed to identify the impact of diabetes on immunotherapy of PAAD by conducting a comparative genomics analysis. Experimental Design We analyzed levels 3 PAAD genomics data (RNAseq, miRNAseq, DNA methylation, somatic copy number and somatic mutation) from TCGA and Firehose. The differential molecular profiles in PAAD with/out diabetes were performed by the differential gene expression, pathway analysis, epigenetic regulation, somatic copy number alteration and somatic gene mutation. Results Differential gene expression analysis revealed a strong enrichment of immunogenic signature genes in diabetic individuals including PD-1 and CTLA4 that were currently targetable for immunotherapy. Pathway analysis further implied that diabetic individuals were defective in immune modulation genes. Somatic copy number aberration (SCNA) analysis showed a higher frequency of amplification and deletion occurred in the cohort without diabetes. Integrative analysis revealed strong association between differential gene expression and epigenetic regulations, however seemed not affected by SCNAs. Importantly, our somatic mutation analysis showed that the occurrence of diabetes in PAAD was associated with a large set of gene mutations encoding genes participating in immune modulation. Conclusions Our analysis reveals the impact of diabetes on immunodeficiency in PAAD patients and provides novel insights into new therapeutic opportunities.

show abstract

Prognostic value of PDL1 expression in pancreatic cancer

Cited by 81 publications

References 77 publications

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

Ex Vivo PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA-Specific T Cells in Pancreatic Cancer Patients

Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics

Contact Info

Product

Resources

About