Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Jan. 2, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. The tumor immune microenvironment (TIME) formed by interactions among cancer cells, cancer-associated fibroblasts (CAF), and extracellular matrix (ECM) components drives PDAC in a more immunosuppressive direction: this major cause therapy resistance poor prognosis. In recent years, research has advanced our understanding signaling mechanism which TIME interact with evolution immunophenotyping. Through revolutionary technologies such as single-cell sequencing, we have gone from simply classifying PDACs “cold” “hot” to comprehensive approach immunophenotyping that considers all cells components. This key improving clinical efficacy treatments. review, elaborate on various PDAC, mechanisms underlying their interactions, latest into A deep these network will contribute effective combination TIME-based therapeutic approaches, checkpoint inhibitors (ICI), adoptive cell therapy, therapies targeting myeloid CAF reprogramming, stromal normalization. By selecting appropriate integrated based precise immunophenotyping, significant advances future treatment are possible.

Language: Английский

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Precision treatment of pancreatic ductal adenocarcinoma

Cancer Letters, Journal Year: 2024, Volume and Issue: 585, P. 216636 - 216636

Published: Jan. 25, 2024

Language: Английский

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Microbiome and pancreatic cancer: time to think about chemotherapy

Gut Microbes, Journal Year: 2024, Volume and Issue: 16(1)

Published: July 18, 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by late diagnosis, rapid progression, and high mortality rate. Its complex biology, dense, stromal tumor environment with an immunosuppressive milieu, contributes to resistance against standard treatments like chemotherapy radiation. This comprehensive review explores the dynamic role of microbiome in modulating efficacy outcomes PDAC. It delves into microbiome's impact on drug metabolism resistance, interaction between microbial elements, drugs, human biology. We also highlight significance specific bacterial species enzymes influencing action immune response microenvironment. Cutting-edge methodologies, including artificial intelligence, low-biomass analysis patient-derived organoid models, are discussed, offering insights nuanced interactions microbes cells. The potential microbiome-based interventions as adjuncts conventional PDAC paving way for personalized therapy approaches. synthesizes recent research provide in-depth understanding how affects efficacy. focuses elucidating key mechanisms identifying existing knowledge gaps. Addressing these gaps crucial enhancing medicine refining treatment strategies, ultimately improving patient outcomes.

Language: Английский

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Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 22, 2024

Abstract Senescent cells within tumors and their stroma exert complex pro- anti-tumorigenic functions. However, the identities traits of these cells, potential for improving cancer therapy through targeting, remain poorly characterized. Here, we identify a senescent subset previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) premalignant lesions mice humans. CAFs isolated from mouse humans expressed elevated levels immune-regulatory genes. Depletion CAFs, either genetically or using Bcl-2 inhibitor ABT-199 (venetoclax), increased proportion activated CD8 + T carcinomas, whereas induction CAF senescence had opposite effect. Combining with an immune checkpoint regimen significantly reduced tumor burden. These results indicate that PDAC limit numbers cytotoxic suggest targeted elimination senolytic treatment may enhance immunotherapy.

Language: Английский

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Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Language: Английский

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VSIG4+ tumor-associated macrophages mediate neutrophil infiltration and impair antigen-specific immunity in aggressive cancers through epigenetic regulation of SPP1

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

Published: Feb. 7, 2025

V-set and immunoglobulin domain-containing 4 (VSIG4) positive tumor-associated macrophage (VSIG4+ TAM) is an immunosuppressive subpopulation newly identified in aggressive cancers. However, the mechanism how VSIG4+ TAMs mediate immune evasion cancers have not been fully elucidated. In our study, we found targeting by VSIG4 deficiency or blockade remarkably limited tumor growth metastasis, especially those derived from anaplastic thyroid cancer (ATC) pancreatic cancer, two extremely types. Moreover, combination of with a BRAF inhibitor synergistically enhanced anti-tumor activity ATC-tumor bearing mice. recovered antigen presentation (B2m, H2-k1, H2-d1) activated antigen-specific CD8+ T cells promoting their vivo proliferation intratumoral infiltration. Notably, loss significantly reduced production lactate histone H3 lysine 18 lactylation, resulting decreased transcription SPP1 mediated STAT3, which collectively disrupted cell-cell interactions between neutrophils. Further boosted activity. Overall, studies demonstrate epigenetic regulation function confers on alternative pattern, beyond checkpoint role VSIG4, to shape microenvironment impair immunity against

Language: Английский

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Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via exosomes in gastrointestinal tumors

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 23, 2024

Gastrointestinal (GI) tumors are a significant global health threat, with high rates of morbidity and mortality. Exosomes contain various biologically active molecules like nucleic acids, proteins, lipids can serve as messengers for intercellular communication. They play critical roles in the exchange information between tumor cells microenvironment (TME). The TME consists mesenchymal components extracellular matrix (ECM), fibroblasts being most abundant cell type mesenchyme. Cancer-associated (CAFs) derived from normal stem that activated TME. CAFs secrete exosomes to modulate proliferation, invasion, migration, drug resistance, other biological processes tumors. Additionally, manipulate function behavior through direct cell-cell interactions. This review provides summary crosstalk GI exosomes, along potential underlying mechanisms.

Language: Английский

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Unbiasedly decoding the tumor microenvironment with single-cell multiomics analysis in pancreatic cancer

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: July 9, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. Research on the tumor microenvironment (TME) of PDAC has propelled development immunotherapeutic targeted strategies promising future. The emergence single-cell sequencing mass spectrometry technologies, coupled spatial omics, collectively revealed heterogeneity TME from multiomics perspective, outlined trajectories cell lineages, important functions previously underrated myeloid cells stroma cells. Concurrently, these findings necessitated more refined annotations biological at cluster or level. Precise identification all clusters urgently needed to determine whether they have been investigated adequately identify target antitumor potential, design compatible treatment strategies, resistance. Here, we summarize recent research level, an unbiased focus potential classification bases every cellular component within TME, look forward prospects integrating data retrospectively reusing bulk data, hoping provide new insights into TME.

Language: Английский

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Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?

Neuro-Oncology, Journal Year: 2023, Volume and Issue: 26(2), P. 211 - 225

Published: Nov. 23, 2023

Abstract Glioblastoma (GBM)’s median overall survival is almost 21 months. Six phase 3 immunotherapy clinical trials have recently been published, yet 5/6 did not meet approval by regulatory bodies. For the sixth, uncertain. Trial failures result from multiple factors, ranging intrinsic tumor biology to trial design. Understanding and basic science of these 6 compelled other immunotherapies reaching point advanced testing. We need understand more in human GBMs early trials: “window opportunity” design may be best complex changes brought about immunotherapeutic perturbations GBM microenvironment. The convergence increased safety image-guided biopsies with “multi-omics” small cell numbers now permits longitudinal sampling biofluids dissect temporal microenvironment as a function immunotherapy.

Language: Английский

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DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

Gut, Journal Year: 2024, Volume and Issue: 73(10), P. 1684 - 1701

Published: June 4, 2024

Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours stromal compartments in order to be effective. Here we investigate whether dual specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria represent a promising anticancer target PDAC.

Language: Английский

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