Immunotherapy in Pancreatic Adenocarcinoma: Beyond “Copy/Paste”

Hester, Robert Harrison; Mazur, Paweł K.; McAllister, Florencia

doi:10.1158/1078-0432.ccr-18-0900

Cited by 32 publications

(29 citation statements)

References 131 publications

(133 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, to date, a limited fraction of individuals with pancreatic cancer appear to have actionable genetic alterations, including BRCA1 and BRCA2 mutations, neurotrophic receptor tyrosine kinase (NTRK) gene fusions, and microsatellite instability (MSI)-high [11,17,[21][22][23][24][25][26]. In addition, the single use of immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PDCD1), CD274 (also known as programmed cell death 1 ligand 1, PD-L1, or B7-H1), and cytotoxic T lymphocyte-associated protein 4 (CTLA4) has shown no effectiveness in metastatic pancreatic cancers [27]. Therefore, many preclinical and translational studies are ongoing to discover potential vulnerabilities and therapeutic opportunities to treat PDAC [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

Masugi

2022

Cancers

View full text Add to dashboard Cite

Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell–cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.

show abstract

Section: Introductionmentioning

confidence: 99%

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

Masugi

2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Meanwhile, immunotherapy treatment efficacy is limited in pancreatic cancer because of the functional and structural barrier imposed by the stroma components. 40 So bodies of cell death induced by pyroptosis may contribute to the structural barrier in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis of Prognostic Value of Pyroptosis-Related Genes and Its Effect on Immune Cell Infiltration in Pancreatic Adenocarcinoma

Wang¹,

Zhang²,

Shao³

et al. 2022

IJGM

View full text Add to dashboard Cite

Purpose Pancreatic adenocarcinoma has a poor prognosis and chemotherapy has its limitation due to tumor heterogeneity. It is essential to find novel targets involving in tumorigenesis of pancreatic adenocarcinoma. Growing evidences indicated that pyroptosis is involved in tumorigenesis of many cancers, but the relationship between pyroptosis and pancreatic adenocarcinoma still remains to be elucidated. Our object is to explore whether pyroptosis-related different expression genes have association with survivals of pancreatic adenocarcinoma patients and the mechanism they may participate in. Besides, we also analyzed their effect on immune cell infiltration in tumor microenvironment. Patients and Methods We used the bioinformatic analysis tool including GEPIA, cBioPortal, STRING, GeneMANIA, R software 4.03 and TIMER2.0 to investigate the different expression, prognostic value, protein-protein interaction, gene ontology, pathway and effect of immune cell infiltration of pyroptosis-related genes in PAAD. Results Many pyroptosis-related genes express differently between pancreatic adenocarcinoma and normal tissues and they are associated with survival of PAAD. GABARAP and IL18 may play a key role in tumorigenesis of PAAD, for they are connected with overall survival, disease free survival and pathological stages at the same time. The function of pyroptosis-related genes includes cytokine production, endopeptidase activity, regulation of inflammation and inflammasome complex and pyroptosis-related genes have effect on immune cells infiltration in PAAD microenvironment. Conclusion Lots of pyroptosis-related DEGs may get involved in pathogenesis of PAAD and their high expression have an effect on survival. GABARAP and IL18 could be valuable research targets of PAAD.

show abstract

“…Drug development in PDAC is challenging, as modest results of immunotherapy in this pathology points out. Although several reasons for this lack of results have been proposed (49), the inclusion of unselected patients in clinical trials, regarding its molecular features, may be a hidden factor, point out the need of taking molecular heterogeneity of PDAC into account in future developments. Our results suggest some therapeutic strategies to follow up in each proteomics subtype.…”

Section: Discussionmentioning

confidence: 99%

Identification of carcinogenesis and tumor progression processes in pancreatic ductal adenocarcinoma using high-throughput proteomics

Trilla-Fuertes

Gámez‐Pozo

Lumbreras-Herrera

et al. 2022

Preprint

View full text Add to dashboard Cite

Pancreatic adenocarcinoma (PDAC) is an aggressive disease with an overall 5 year-survival rate of just 5%. A better understanding of both the carcinogenesis processes and the mechanisms of progression of PDAC disease is mandatory. Proteomics offers complementary information to genomics, measuring the direct effectors of the biological processes. From a cohort of 110 PDAC patients treated with surgery and adjuvant therapy, 52 patients, of which primary tumor and normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases were available, were selected for the study. Proteins were extracted from small punches obtained from formalin fixed, paraffin embedded tissue, and analyzed by LC-MS/MS using a data-independent acquisition approach. Protein expression data was analyzed using probabilistic graphical models, allowing functional characterization. Functional node activities were calculated as the mean of expression of those proteins related to the main function of each node. Comparisons between groups were done using linear mixed models. First, analyzing the tumor tissue, three proteomics subtypes were defined: T1 (32% of patients) presented higher activity of adhesion and complement activation nodes, T2 (34%) had higher mitochondrial and metabolic node activity, and T3 (34%) had higher nucleoplasm node activity. Second, relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. We found differences between T1 PanIN and primary tumors in adhesion, translation, mitochondria and pancreatic secretion nodes, suggesting an involvement of these processes in tumor development. Differences between tumors and lymph nodes, related to tumor progression, were identified in nucleoplasm, translation, adhesion, extracellular matrix, and complement activation nodes. Mitochondria and metabolism nodes had differential activity between T2 normal tissue, PanIN and tumors, and also between tumors and lymph nodes. T3 analyses point out that nucleoplasm, metabolism and mitochondria, and extracellular matrix nodes could be involved in T3 tumors carcinogenesis. Interestingly, identified processes were different between the three proteomics subtypes suggesting that the motor of the disease is characteristic of each subtype. Additionally, these proteomics subtypes were validated into the PDAC TCGA cohort. In this study, three PDAC proteomics subtypes were defined, an adhesion-related subtype (T1), a metabolic-related subtype (T2), and a nucleoplasm subtype (T3). We also suggest several biological processes involved in tumor development and progression exclusive of each proteomics subtype. These biological processes could be relevant as a guide to select candidates for future tailored therapeutics treatments in PDAC. Proteomics data are available via ProteomeXchange with identifier PXD032076.

show abstract

Immunotherapy in Pancreatic Adenocarcinoma: Beyond “Copy/Paste”

Cited by 32 publications

References 131 publications

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

Bioinformatic Analysis of Prognostic Value of Pyroptosis-Related Genes and Its Effect on Immune Cell Infiltration in Pancreatic Adenocarcinoma

Identification of carcinogenesis and tumor progression processes in pancreatic ductal adenocarcinoma using high-throughput proteomics

Contact Info

Product

Resources

About