Neoadjuvant therapy-induced remodeling of tumor immune microenvironment in pancreatic ductal adenocarcinoma: a spatial and digital pathology analysis

Virchows Archiv, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Neoadjuvant therapy (NAT) is the standard of care for borderline-resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC). It can be used to treat resectable PDAC. This study aimed investigate how NAT remodels tumor immune microenvironment (TIME) whether this remodeling translates into survival benefits. We performed spatial digital pathology analysis 27 upfront resection patients (naïve group) 39 age-, gender-, stage-matched who had surgery after (NAT group). AI-assisted was annotate cancer cells CD8 + T lymphocytes. Spatial correlation between lymphocytes each case assessed using point pattern analysis, followed by generalized linear modeling (GLM) quadrat counts cells, with as independent variable. The regression coefficient quantify strength their then further association patient survival. analyses showed that group, compared naïve increased suggesting enhanced effector cell-cancer cell engagement in patients. Additionally, a higher degree two improved after-surgery Through new methodological framework takes advantage our has successfully captured subtle effects NAT-induced TIME its impact on prognosis PDAC

Language: Английский

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CXCL6-CXCR2 axis-mediated PD-L2+ mast cell accumulation shapes the immunosuppressive microenvironment in osteosarcoma

Heliyon, Journal Year: 2024, Volume and Issue: 10(14), P. e34290 - e34290

Published: July 1, 2024

Osteosarcoma (OS) is the most common primary bone malignancy and has a high propensity for local invasion metastasis. The tumour microenvironment of OS infiltrated by large number immune cells, which play crucial role in its progression prognosis. Mast cells are important innate stroma exhibit different phenotypes diverse microenvironments. However, underlying mechanisms mast cell accumulation phenotypic characteristics remain poorly understood. In this article, we found first time that osteosarcoma tissue was modulated CXCL6-CXCR2 axis infiltrating significantly greater tissues than adjacent nontumour tissues. These tumour-infiltrating express levels immunosuppressive molecule PD-L2, survival analyses revealed patients PD-L2+ high-expression group had worse vitro, were induced to PD-L2 time- dose-dependent manner using culture supernatants mimic microenvironment. Mechanistic studies cell-derived G-CSF expression activating STAT3. Importantly, overexpressing inhibit tumour-specific CD8+ T-cell proliferation tumour-killing cytokine secretion, reversed blocking on cells. Therefore, our findings provide new insight into tumorigenic roles as well novel mechanism PD-L2-expressing mediate tolerance.

Language: Английский

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Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(9), P. 1207 - 1207

Published: Sept. 13, 2024

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on disease's pathophysiology, involved tissues, cell populations, and cellular components, drugs often have to overcome several biological reach their target cells become effective in specific compartment. Human are incredibly diverse include multiple layers protection obstruction. Importantly, not only found at organ/tissue level, but also structures such as outer plasma membrane, endolysosomal machinery, nuclear envelope. Nowadays, clinicians access broad arsenal therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such monoclonal antibodies hormones), nucleic-acid-based therapeutics, antibody-drug conjugates (ADCs), modern viral-vector-mediated gene therapy. In past decade, therapeutic landscape has been changing rapidly, giving rise multitude therapy approaches. 2018, FDA approval patisiran paved way interfering RNAs (siRNAs) novel class which-upon drug delivery cells-allow elegantly regulate post-transcriptional expression. The recent approvals valoctocogene roxaparvovec etranacogene dezaparvovec treatment hemophilia A B, respectively, mark breakthrough viral-vector-based new tool cure disease. highly medicines methods mRNA-based cancer vaccines exosome-targeted is verge entering market range conditions. this review, we provide insights into three different disease entities, which clinically, scientifically, socioeconomically impactful given many technological advancements: acquired immunodeficiency syndrome (AIDS) predominant infectious disease, pancreatic carcinoma one most lethal solid cancers, A/B hereditary genetic disorder. Our primary objective highlight overarching principles that can be identified across areas. second goal showcase approaches designed cross disease-specific promising effectively treating context, will exemplify how right selection category vehicle, mode administration, target(s) help various prevent, treat,

Language: Английский

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B cell c-Maf signaling promotes tumor progression in animal models of pancreatic cancer and melanoma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 2, 2024

Abstract Background The role of B cells in anti-tumor immunity remains controversial, with studies suggesting the pro-tumor and activity. This controversy may be due to heterogeneity cell populations, as balance among subtypes impact tumor progression. immunosuppressive regulatory (Breg) release IL-10 but only represent a minor population. Additionally, tumor-specific antibodies (Ab) also exhibit function dependent on Ab isotype. Transcription factor c-Maf has been suggested contribute regulation Breg, signaling regulating antibody responses remain unknown. Methods Conditional knockout (KO) control mice were used establish KPC pancreatic cancer model B16.F10 melanoma model. Tumor progression was evaluated. T phenotypes determined by flow cytometry, mass cytokine/chemokine profiling. Differentially expressed genes examined using RNA-seq. Peripheral blood samples collected from healthy donors patients for phenotyping. Results Compared spleen lymph nodes, pancreas exhibited significantly less follicular phenotype higher production naïve mice. deficiency resulted significant reduction CD9 + IL-10-producing Breg pancreas. PDAC accumulation circulating Notably, delayed pro-inflammatory cells. Further, volume increased effective tumor-draining node (TDLN) observed KO RNA-seq analysis isolated revealed that modulates immunoglobulin (Ig)-associated specific production. We furthermore demonstrated c-Maf-positive subsets increase after incubation IL-4 CD40L peripheral patients. Conclusion Our study highlights drives through modulation inflammatory responses, responses. What is already known this topic net effect depends various subtypes. (Breg), adds shown melanoma. defined different mechanisms two models. Specifically, tumor-bearing draining nodes How might affect research, practice or policy These indicate inhibition novel promising approach immunotherapy

Language: Английский

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Breakthroughs in nanoparticle-based strategies for pancreatic cancer therapy

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: unknown, P. 116685 - 116685

Published: Nov. 1, 2024

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, mainly due to its high heterogeneity, resistance therapy and late diagnosis, with a 5-year survival rate less than 10%. This dismal prognosis has promoted strategies develop more effective treatments. Nanoparticle-based have emerged, in last decades, as great opportunity because they can enhance drug delivery promote controlled release, presenting lower side effects conventional therapeutic regimens. Moreover, nanoparticles often be modified target specific cells or achieve sustained release drugs into tumor. However, very few nanoparticle-based therapies are clinically approved. Concretely for pancreatic cancer treatment only two nanoformulations been approved by US Food Drug Administration (FDA) European Medicines Agency (EMA) so far. Clinical translation remains challenge modern medicine, particular therapy, complexity disease, lack studies performed relevant vitro vivo models. In this review, we summarized most recent clinical trials using formulations PDAC, giving small context diverse types employed advancements field.

Language: Английский

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Organoids, tissue slices and organotypic cultures: advancing our understanding of pancreatic ductal adenocarcinoma through in vitro and ex vivo models

Seminars in Cancer Biology, Journal Year: 2024, Volume and Issue: 109, P. 10 - 24

Published: Dec. 25, 2024

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses all common solid cancers. For large majority PDAC patients, only systemic therapies with very limited efficacy are indicated. In addition, immunotherapies have not brought advances seen in other cancer types. Several key characteristics contribute to poor treatment outcomes, and this review, we will discuss how these best captured currently available ex vivo or vitro model systems. instance, is hallmarked by a highly desmoplastic immune-suppressed tumor microenvironment that impacts disease progression therapy resistance. Also, differences biology exist between within tumors, complicating decisions. Furthermore, high propensity for locally invasive metastatic growth. The use animal models often desirable feasible several systems been developed, such as organotypic cocultures tissue slices, among others. However, absence full host organism ability accurately capture outcomes PDAC. We caveats advantages context PDAC's provide recommendations on choice possibilities optimization. These considerations should be researchers aiming study setting.

Language: Английский

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A mathematical model for pancreatic cancer during intraepithelial neoplasia

Royal Society Open Science, Journal Year: 2024, Volume and Issue: 11(10)

Published: Oct. 1, 2024

Cancer is the result of complex interactions intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming reorganization. The evolution any type cancer emerges from role microenvironmental conditions their impact some molecular complexes on certain signalling pathways. understanding early onset requires a multiscale analysis cellular microenvironment. In this paper, we analyse qualitative model pancreatic adenocarcinoma by modelling microenvironment through elastic intercellular communication mechanisms, such as growth factors cytokines. We focus low-grade dysplasia (PanIN 1) moderate 2) stages adenocarcinoma. To end, propose gene-regulatory network associated with processes proliferation apoptosis cells its kinetics in terms delayed differential equations mimic development. Likewise, couple cycle spatial distribution transport show that triggered inflammatory processes. oncogene RAS may be an important target for developing anti-inflammatory strategies limit emergence more aggressive adenocarcinomas.

Language: Английский

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B cell c-Maf signaling promotes tumor progression in animal models of pancreatic cancer and melanoma

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(11), P. e009861 - e009861

Published: Nov. 1, 2024

Background The role of B cells in antitumor immunity remains controversial, with studies suggesting the protumor and activity. This controversy may be due to heterogeneity cell populations, as balance among subtypes impact tumor progression. immunosuppressive regulatory (Breg) release interleukin 10 (IL-10) but only represent a minor population. Additionally, tumor-specific antibodies (Abs) also exhibit functions dependent on Ab isotype. Transcription factor c-Maf has been suggested contribute regulation IL-10 Breg, signaling regulating responses unknown. Methods Conditional knockout (KO) control mice were used establish KPC pancreatic cancer model B16.F10 melanoma model. Tumor progression was evaluated. T phenotypes determined by flow cytometry, mass cytokine/chemokine profiling. Differentially expressed genes examined using RNA sequencing (RNA-seq). Peripheral blood samples collected from healthy donors patients for phenotyping. Results Compared spleen lymph nodes (LN), pancreas exhibited significantly less follicular phenotype higher production naïve mice. deficiency resulted significant reduction CD9 + IL-10-producing Breg pancreas. Pancreatic ductal adenocarcinoma (PDAC) accumulation circulating Notably, delayed PDAC proinflammatory cells. Further, volume increased effective tumor-draining LN observed KO RNA-seq analysis isolated revealed that modulates immunoglobulin-associated production. We furthermore demonstrated c-Maf-positive subsets an increase after incubation IL-4 CD40L peripheral melanoma. Conclusion Our study highlights drives through modulation inflammatory responses, responses.

Language: Английский

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