The Role of Immunotherapy in Pancreatic Cancer

Mukherji, Reetu; Debnath, Dipanjan; Hartley, Marion L.; Noel, Marcus Smith

doi:10.3390/curroncol29100541

Cited by 48 publications

(25 citation statements)

References 167 publications

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“…In order to investigate whether the PD-1/PD-L1 inhibitory axis is involved in the HMF mediated impairment of CD8 + T cells in our stroma enriched PDAC spheroid models, treatment with the clinically validated PD-L1 and PD-1 inhibitors Durvalumab and Pembrolizumab, respectively, was performed. In line with results from recent clinical trials that tested the benefit of ICI for the treatment of PDAC patients ( 5 , 31 , 40 ), neither Durvalumab nor Pembrolizumab treatment improved the effector phenotype of CD8 + T cells and increased PDAC cell death in our human stroma enriched 3D PDAC model. In this context, it has to be critically noted that based on our current imaging modalities, no reliable conclusion can be made whether CD8 + T cells infiltrate differentially into HMF enriched spheroids compared to monoculture PDAC spheroids and whether this is impacted by ICI.…”

Section: Discussionsupporting

confidence: 87%

“…PDAC is characterized by a low mutational burden and regarded as a so called “cold” or “excluded” tumor with a general low T cell infiltration into the tumor ( 30 ). In addition, CD8 + T cells are often defined as exhausted and show a higher resistance towards ICI treatment ( 31 , 32 ). Altogether, these findings provide an explanation for ICI resistance of this tumor ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

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Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma

et al. 2023

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IntroductionPancreatic ductal adenocarcinoma (PDAC) represents the 4th most common cause of cancer-related deaths in Western countries. Most patients are diagnosed at advanced stages, often already with metastases. The main site of metastasis is the liver and hepatic myofibroblasts (HMF) play a pivotal role in metastatic outgrowth. Immune checkpoint inhibitors (ICI) targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) improved treatment of several cancers but not of PDAC. Therefore, this study aimed to better understand the impact of HMF on PD-L1 expression and immune evasion of PDAC cells during liver metastasis.MethodsFormalin-fixed and paraffin embedded biopsy samples or diagnostic resection specimens from liver metastases of 15 PDAC patients were used for immunohistochemical analyses. Serial sections were stained with antibodies directed against Pan-Cytokeratin, αSMA, CD8, and PD-L1. To investigate whether the PD-1/PD-L1 axis and HMF contribute to immune escape of PDAC liver metastases, a stroma enriched 3D spheroid coculture model was established in vitro, using two different PDAC cell lines, HMF, and CD8+ T cells. Here, functional and flow cytometry analyses were conducted.ResultsImmunohistochemical analysis of liver tissue sections of PDAC patients revealed that HMF represent an abundant stroma population in liver metastases, with clear differences in the spatial distribution in small (1500 µm) and large (> 1500 μm) metastases. In the latter, PD-L1 expression was mainly located at the invasion front or evenly distributed, while small metastases either lacked PD-L1 expression or showed mostly weak expression in the center. Double stainings revealed that PD-L1 is predominantly expressed by stromal cells, especially HMF. Small liver metastases with no or low PD-L1 expression comprised more CD8+ T cells in the tumor center, while large metastases exhibiting stronger PD-L1 expression comprised less CD8+ T cells being mostly located at the invasion front. HMF-enriched spheroid cocultures with different ratios of PDAC cells and HMF well mimicking conditions of hepatic metastases in situ. Here, HMF impaired the release of effector molecules by CD8+ T cells and the induction of PDAC cell death, an effect that was dependent on the amount of HMF but also of PDAC cells. ICI treatment led to elevated secretion of distinct CD8+ T cell effector molecules but did not increase PDAC cell death under either spheroid condition.ConclusionOur findings indicate a spatial reorganization of HMF, CD8+ T cells, and PD-L1 expression during progression of PDAC liver metastases. Furthermore, HMF potently impair the effector phenotype of CD8+ T cells but the PD-L1/PD-1 axis apparently plays a minor role in this scenario suggesting that immune evasion of PDAC liver metastases relies on other immunosuppressive mechanisms.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma

et al. 2023

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“…It enhances the patient's immune response, enabling the body to better fight against tumors. Immunotherapy can be implemented through various methods, including antibodies targeting protein molecules, cell vaccines, and cytokines to activate the immune system (Brouwer et al, 2021; D. Cao, Song, et al, 2021; Mukherji et al, 2022; Sunami & Kleeff, 2019).…”

Section: Sdt For Pancreatic Cancermentioning

confidence: 99%

Recent advances in sonodynamic therapy strategies for pancreatic cancer

Cheng,

Ming,

Cao

et al. 2024

WIREs Nanomed Nanobiotechnol

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Pancreatic cancer, a prevalent malignancy of the digestive system, has a poor 5‐year survival rate of around 10%. Although numerous minimally invasive alternative treatments, including photothermal therapy and photodynamic therapy, have shown effectiveness compared with traditional surgical procedures, radiotherapy, and chemotherapy. However, the application of these alternative treatments is constrained by their depth of penetration, making it challenging to treat pancreatic cancer situated deep within the tissue. Sonodynamic therapy (SDT) has emerged as a promising minimally invasive therapy method that is particularly potent against deep‐seated tumors such as pancreatic cancer. However, the unique characteristics of pancreatic cancer, including a dense surrounding matrix, high reductivity, and a hypoxic tumor microenvironment, impede the efficient application of SDT. Thus, to guide the evolution of SDT for pancreatic cancer therapy, this review addresses these challenges, examines current strategies for effective SDT enhancement for pancreatic cancer, and investigates potential future advances to boost clinical applicability.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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“…Consequently, traditional immunotherapies have shown relatively poor efficacy in their treatment. Single immunotherapies such as immune checkpoint inhibitors have demonstrated limited effectiveness in the majority of PDAC patients [40,41]. Therefore, it is crucial to develop strategies that can transform the immune environment of PDAC to enhance immune cell infiltration and antitumor immune responses.…”

Section: Making Immunologically "Desert" Tumor Responsive To Immunoth...mentioning

confidence: 99%

Making incurable pancreatic cancer curable

An,

Xie,

Xie

2023

Malignancy Spectrum

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Pancreatic cancer is one of the deadliest malignancies, with limited effectiveness of standard therapies, resulting in little improvement in the 5‐year survival rate over the past few decades. However, advanced radiotherapy techniques and emerging treatment modalities, such as immunotherapy and targeted therapy, are showing tremendous potential as effective treatment options for pancreatic cancer patients who were previously considered incurable. This review summarizes the current advances and challenges in pancreatic cancer treatment strategies and proposes further optimization directions, aiming to provide insights into the cure of incurable pancreatic cancer.

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The Role of Immunotherapy in Pancreatic Cancer

Cited by 48 publications

References 167 publications

Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma

Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma

Recent advances in sonodynamic therapy strategies for pancreatic cancer

Making incurable pancreatic cancer curable

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