Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: July 24, 2023

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared the localized tumors, current standard-of-care therapies have failed improve survival patients with metastatic PDAC, that necessecitates exploration novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) vaccines emerged promising treatment modalities in certain cancers, limited responses been achieved PDAC. Therefore, specific mechanisms regulating response immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, microbiome persists throughout PDAC progression, allowing neoplastic cells grow locally metastasize distantly. escaping host surveillance are unique molecular, immunological, metabolic characteristics. Following chemokine exosomal guidance, these organ-specific pre-metastatic niches (PMNs) constituted local resident cells, stromal fibroblasts, suppressive metastasis-associated macrophages, neutrophils, myeloid-derived suppressor cells. differs from primary tumors cell composition, functionality, metabolism. Thus far, multiple molecular pathways, distinct identified dampen effector functions, confounding This review describes major immunoregulatory pathways contribute progression limit outcomes Overall, we highlight vulnerabilities attributable factors discuss whether targeting immunological "hot spots" could immunotherapies.

Language: Английский

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Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 2, 2024

Pancreatic cancer is a highly aggressive malignant tumor, that becoming increasingly common in recent years. Despite advances intensive treatment modalities including surgery, radiotherapy, biological therapy, and targeted the overall survival rate has not significantly improved patients with pancreatic cancer. This may be attributed to insidious onset, unknown pathophysiology, poor prognosis of disease. It therefore essential identify develop more effective safer treatments for Tumor immunotherapy new fourth pillar anti-tumor therapy after chemotherapy. Significant progress made use wide variety tumors years; breakthrough also been review describes immune checkpoint inhibitors, vaccines, adoptive cell oncolytic virus, matrix-depletion therapies At same time, some potential biomarkers combinations are discussed. The molecular mechanisms various immunotherapies have elucidated, their clinical applications highlighted. current challenges associated proposed strategies hold promise overcoming these limitations discussed, aim offering insights into

Language: Английский

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Intracellular Magnetic Hyperthermia Enables Concurrent Down-Regulation of CD47 and SIRPα To Potentiate Antitumor Immunity

Nano Letters, Journal Year: 2024, Volume and Issue: 24(9), P. 2894 - 2903

Published: Feb. 26, 2024

Harnessing the potential of tumor-associated macrophages (TAMs) to engulf tumor cells offers promising avenues for cancer therapy. Targeting phagocytosis checkpoints, particularly CD47-signal regulatory protein α (SIRPα) axis, is crucial modulating TAM activity. However, single checkpoint inhibition has shown a limited efficacy. In this study, we demonstrate that ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-mediated magnetic hyperthermia effectively suppresses expression CD47 on Hepa1-6 and SIRPα receptor macrophages, which disrupts CD47-SIRPα interaction. FVIO-mediated also induces immunogenic cell death polarizes TAMs toward M1 phenotype. These changes collectively bolster phagocytic ability eliminate cells. Furthermore, concurrently escalates cytotoxic T lymphocyte levels diminishes levels. Our findings reveal novel approach dual down-regulation SIRPα, reshaping microenvironment stimulate immune responses, culminating in significant antitumor

Language: Английский

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Interplay of immune modulation, adaptive response and hormesis: Suggestive of threshold for clinical manifestation of effects of ionizing radiation at low doses?

The Science of The Total Environment, Journal Year: 2024, Volume and Issue: 917, P. 170178 - 170178

Published: Jan. 25, 2024

Language: Английский

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Multiparametric MRI for Assessment of the Biological Invasiveness and Prognosis of Pancreatic Ductal Adenocarcinoma in the Era of Artificial Intelligence

Journal of Magnetic Resonance Imaging, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest malignant tumor, with a grim 5‐year overall survival rate of about 12%. As its incidence and mortality rates rise, it likely to become second‐leading cause cancer‐related death. The radiological assessment determined stage management PDAC. However, highly heterogeneous disease complexity tumor microenvironment, challenging adequately reflect biological aggressiveness prognosis accurately through morphological evaluation alone. With dramatic development artificial intelligence (AI), multiparametric magnetic resonance imaging (mpMRI) using specific contrast media special techniques can provide functional information high image quality powerful tool in quantifying intratumor characteristics. Besides, AI has been widespread field medical analysis. Radiomics high‐throughput mining quantitative features from that enables data be extracted applied for better decision support. Deep learning subset neural network algorithms automatically learn feature representations data. AI‐enabled biomarkers mpMRI have enormous promise bridge gap between personalized medicine demonstrate huge advantages predicting characteristics current AI‐based models PDAC operate mainly realm single modality relatively small sample size, technical reproducibility interpretation present barrage new potential challenges. In future, integration multi‐omics data, such as radiomics genomics, alongside establishment standardized analytical frameworks will opportunities increase robustness interpretability bring these closer clinical practice. Evidence Level 3 Technical Efficacy Stage 4

Language: Английский

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CASC8 activates the pentose phosphate pathway to inhibit disulfidptosis in pancreatic ductal adenocarcinoma though the c-Myc-GLUT1 axis

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Jan. 27, 2025

Abstract Purpose Glucose starvation induces the accumulation of disulfides and F-actin collapse in cells with high expression SLC7A11, a phenomenon termed disulfidptosis. This study aimed to confirm existence disulfidptosis pancreatic ductal adenocarcinoma (PDAC) elucidate role Cancer Susceptibility 8 (CASC8) this process. Methods The PDAC was assessed using flow cytometry staining. CASC8 its clinical correlations were analyzed data from Genome Atlas (TCGA) further verified by chromogenic situ hybridization assay tissues. Cells knockdown overexpression subjected cell viability, EdU, transwell assays, used establish subcutaneous orthotopic tumor models. Disulfidptosis detected immunofluorescence assays. RNA sequencing metabolomics analysis performed determine metabolic pathways which significantly affected after knockdown. We glucose consumption NADP + /NADPH ratio investigate alterations profiles. immunoprecipitation combined fluorescence identify protein-RNA interactions. Protein stability, western blotting quantitative real-time PCR assays reveal potential molecular mechanism. Results observed could be rescued inhibitors. higher samples compared normal tissue. High correlated poor prognosis for patients contributed cancer progression vitro vivo. Furthermore, associated resistance under conditions PDAC. Mechanistically, interacted c-Myc enhance stability protein, leading activation pentose phosphate pathway, reduction ultimately inhibiting conditions. Conclusions provides evidence reveals upregulation malignancy. we demonstrate that acts as crucial regulator pathway disulfidptosis, thereby promoting progression.

Language: Английский

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Claudin 18 (43–14A clone) expression in pancreatic ductal adenocarcinoma: Assessment of a potential clinical biomarker for zolbetuximab therapy

Translational Oncology, Journal Year: 2025, Volume and Issue: 55, P. 102362 - 102362

Published: March 20, 2025

Language: Английский

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Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma

Cancers, Journal Year: 2023, Volume and Issue: 15(17), P. 4265 - 4265

Published: Aug. 25, 2023

Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause death. Poor prognosis a result late presentation, lack screening tests fact some patients develop resistance chemotherapy radiotherapy. Novel therapies like immunotherapeutics have been recent interest in cancer. However, this field remains its infancy with much unravel. Immunotherapy other targeted yet yield significant progress treating PDAC, primarily due our limited understanding disease immune mechanisms intricate interactions tumour microenvironment (TME). In review we provide an overview current novel immunotherapies which studied We discuss their mechanisms, evidence available as well limitations such therapies. showcase potential role combining postulate clinical implications hurdles associated use PDAC. Therapies discussed include programmed death checkpoint inhibitors, Cytotoxic T-lymphocyte-associated protein 4, Chimeric Antigen Receptor-T cell therapy, oncolytic viral therapy vaccine including KRAS vaccines, Telomerase Gastrin Vaccines, Survivin-targeting Heat-shock (HSP) peptide complex-based MUC-1 targeting Listeria based vaccines Dendritic cell-based vaccines.

Language: Английский

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Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Cellular Oncology, Journal Year: 2023, Volume and Issue: 46(5), P. 1473 - 1492

Published: May 29, 2023

Language: Английский

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Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights

Current Oncology, Journal Year: 2023, Volume and Issue: 30(4), P. 3871 - 3885

Published: March 30, 2023

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with poor 5-year overall survival rate (~10%). The revolution of immunotherapy in clinical oncology has not substantially changed outcome for patients PDAC. Despite outstanding efforts, neither immune checkpoint inhibitors (ICIs) alone, nor combination chemotherapy or targeted therapies have shown encouraging results. This failure mirrors the lack knowledge about real key players system senescence and complexity tumor microenvironment However, some hope can be derived from PARP-inhibitor combinations, vaccines, CAR-T-cells therapy. In this review, we comprehensively summarize latest updates use ICIs PDAC, focusing on evidence ongoing studies highlighting explanations possible solutions.

Language: Английский

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