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Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGF?1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.

SUBMITTER: Liu J

PROVIDER: S-EPMC6400540 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma.

Liu Jing J Jiang Wenna W Zhao Kaili K Wang Hongwei H Zhou Tianxing T Bai Weiwei W Wang Xiuchao X Zhao Tiansuo T Huang Chongbiao C Gao Song S Qin Tai T Yu Wenwen W Yang Bo B Li Xin X Fu Danqi D Tan Wei W Yang Shengyu S Ren He H Hao Jihui J

The Journal of experimental medicine 20190207 3

Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a ...[more]

PMID: 30733283

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Project description:Pancreatic ductal adenocarcinoma (PDA) is notorious for its poor prognosis. The current mainstay of treatment for PDA is surgical resection followed by adjuvant chemotherapy. However, it is difficult to predict the post-operative outcome because of the lack of reliable markers. The single-nucleotide polymorphism (SNP) of N-acetylgalactosaminyltransferase14 (GALNT14) has been proven to predict the progression-free survival (PFS), overall survival (OS) and response to chemotherapy in various types of gastrointestinal (GI) cancers. However, its role in PDA has not been studied. This study aims to investigate whether the GALNT14 SNP genotype can be a prognostic marker for PDA. A cohort of one hundred and three PDA patients having received surgical resection were retrospectively enrolled. GALNT14 genotypes and the clinicopathological parameters were correlated with postoperative prognosis. The genotype analysis revealed that 19.4%, 60.2% and 20.4% of patients had the GALNT14 "TT", "TG" and "GG" genotypes, respectively. The patients with the "GG" genotype had a mean OS time of 37.1 months (95% confidence interval [CI]: 18.2-56.1) and those with the "non-GG" genotype had a mean OS time of 16.1 months (95% CI: 13.1-19.2). Kaplan-Meier analysis showed that the "GG" genotype had a significantly better OS compared to the "non-GG" genotype (p = 0.005). However, there was no significant difference between the "GG" and "non-GG" genotypes in PFS (p = 0.172). The baseline characteristics between patients with the "GG" and "non-GG" genotypes were compared, and no significant difference was found. Univariate followed by multivariate Cox proportional hazard models demonstrated the GALNT14 "GG" genotype, negative resection margin, and locoregional disease as independent predictors for favorable OS (p = 0.003, p = 0.037, p = 0.021, respectively). Sensitivity analysis was performed in each subgroup to examine the relationship of GALNT14 with different clinicopathological variables and no heterogeneity was found. The GALNT14 "GG" genotype is associated with favorable survival outcome, especially OS, in patients with resected PDA and could serve as a prognostic marker.

Project description:BackgroundPDAC is a highly malignant and immune-suppressive tumor, posing great challenges to therapy.MethodsIn this study, we utilized multi-center RNA sequencing and non-negative matrix factorization clustering (NMF) to identify a group of metabolism-related genes that could effectively predict the immune status and survival (both disease-free survival and overall survival) of pancreatic ductal adenocarcinoma (PDAC) patients. Subsequently, through the integration of single cell sequencing and our center's prospective and retrospective cohort studies, we identified ABHD17C, which possesses metabolic and immune-related characteristics, as a potential biomarker for predicting the prognosis and response to anti-PD1 therapy in PDAC. We then demonstrated how ABHD17C participates in the regulation of the immune microenvironment through in vitro glycolytic function experiments and in vivo animal experiments.ResultsThrough screening for pancreatic cancer metabolic markers and immune status, we identified a critical molecule that inhibits pancreatic cancer survival and prognosis. Further flow cytometry analysis confirmed that ABHD17C is involved in the inhibition of the formation of the immune environment in PDAC. Our research found that ABHD17C participates in the metabolic process of tumor cells in in vitro and in vivo experiments, reshaping the immunosuppressive microenvironment by downregulating the pH value. Furthermore, through LDHA inhibition experiments, we demonstrated that ABHD17C significantly enhances glycolysis and inhibits the formation of the immune suppressive environment. In in vivo experiments, we also validated that ABHD17C overexpression significantly mediates resistance to anti-PD1 therapy and promotes the progression of pancreatic cancer.ConclusionTherefore, ABHD17C may be a novel and effective biomarker for predicting the metabolic status and immune condition of PDAC patients, and provide a potential predictive strategy for anti-PD1 therapy in PDAC.

Project description:Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

Dataset Information

Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma.

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Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma.

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