Fibroblast heterogeneity in pancreatic ductal adenocarcinoma: Perspectives in immunotherapy

Luong, Tha; Golivi, Yuvasri; El‐Rayes, Bassel F.

doi:10.1016/j.cytogfr.2022.09.001

Cited by 9 publications

(6 citation statements)

References 101 publications

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“…The highly heterogeneous CAFs in PDAC infiltrate in large numbers, which are believed to be derived from PSCs, tissue resident fibroblasts, mesenchymal stem cells, and endothelial cells [ 131 ]. Therefore, CAFs are accordingly categorized into multiple subtypes (Fig.…”

Section: More Complete Immunophenotyping: Enrolling the Matrixmentioning

confidence: 99%

“…Interaction with other microenvironment components: During PDAC progression, CAFs exert long-lasting educative effects on the surrounding immune cells, with the overall effect of inhibiting their normal function and inducing a shift towards a pro-tumorigenic phenotype. Previous studies have shown that CAF can promote the differentiation and activation of M2 macrophages through M-CSF, IL-6, and CCL2 [ 131 ]. HIFs mediate the cellular response to hypoxia.…”

Section: More Complete Immunophenotyping: Enrolling the Matrixmentioning

confidence: 99%

“…The timing of drug delivery must be considered, as TGF-β may only exhibit tumor-suppressive functions in the early stages of PDAC. Studies have also found vitamin A analogues and the activation of vitamin D receptors to convert CAFs into a quiescent state before their activity [ 131 ]. Agonists of vitamin D receptor are promising in the future for PDAC treatment, and all-trans retinoic acid has shown some therapeutic efficacy in a phase I trial [ 171 , 172 ].…”

Section: More Complete Immunophenotyping: Enrolling the Matrixmentioning

confidence: 99%

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

Luo,

Wen,

2024

J Exp Clin Cancer Res

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

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Section: More Complete Immunophenotyping: Enrolling the Matrixmentioning

confidence: 99%

Section: More Complete Immunophenotyping: Enrolling the Matrixmentioning

confidence: 99%

Section: More Complete Immunophenotyping: Enrolling the Matrixmentioning

confidence: 99%

See 1 more Smart Citation

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

Luo,

Wen,

2024

J Exp Clin Cancer Res

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“…An improved understanding of pancreatic cancer biology and genetics, including novel information on driver gene alterations, tumor metabolism and the TME, might contribute to attractive and creative effective treatments (31). Immunotherapy has become increasingly utilized in the treatment of PAAD (32). Despite the overwhelming success of immune checkpoint inhibitors in leukemia and melanoma, PAAD is an outlier due to its immunosuppressive TME and poor tumor immunogenicity (33).…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of expression profiles and prognostic significance of the FGF gene family in pancreatic adenocarcinoma

et al. 2022

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Pancreatic adenocarcinoma (PAAD) is a malignant tumor with one of the highest associated mortality rates worldwide, and a 5-year survival rate of <5%. Fibroblast growth factors (FGFs) serve important roles in numerous cellular functions, and dysregulation of FGFs contributes to various cancer types. However, there are few reports on the function of FGFs in PAAD. The Assistant for Clinical Bioinformatics database, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter and Tumor Immune Estimation Resource were utilized to perform the protein-protein interaction network, functional enrichment, univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox, differential expression, prognostic value and immune cell infiltration analyses of FGFs in patients with PAAD. Immunohistochemistry (IHC) was used to verify the predictive value of the model. A total of 22 FGF genes were identified. Based on the results of LASSO Cox regression analysis, a total of six genes, including FGF2, FGF8, FGF9, FGF13, FGF17 and FGF22, were selected for the establishment of the prognostic gene signature. High transcriptional levels of FGF17 and FGF22 were significantly associated with long overall survival. The expression of FGFs was associated with the infiltration of various immune cells. According to univariate and multivariate analyses, FGF2 and FGF8 may be useful independent prognostic biomarkers for the prognosis of patients with PAAD. IHC demonstrated that FGF2 and FGF8 were more highly expressed in PAAD tissues compared with that in normal tissues. The present findings offer a novel understanding for the selection of FGF prognostic biomarkers in PAAD.

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“…Pancreatic adenocarcinoma (PAAD) is a highly lethal tumor due to its relatively late diagnosis, rapid metastatic dissemination, and limited methods of treatment 1 . The American Cancer Society has estimated that, in 2022, 62,210 individuals would develop pancreatic cancer, that 49,830 would die of this disease, and that the 5-year relative survival rate would be 11% 2 .…”

Section: Introductionmentioning

confidence: 99%

Cancer-associated fibroblast-related prognostic signature predicts prognosis and immunotherapy response in pancreatic adenocarcinoma based on single-cell and bulk RNA-sequencing

Chen,

Deng,

Chen

et al. 2023

Sci Rep

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Cancer-associated fibroblasts (CAFs) influence many aspects of pancreatic adenocarcinoma (PAAD) carcinogenesis, including tumor cell proliferation, angiogenesis, invasion, and metastasis. A six-gene prognostic signature was constructed for PAAD based on the 189 CAF marker genes identified in single-cell RNA-sequencing data. Multivariate analyses showed that the risk score was independently prognostic for survival in the TCGA (P < 0.001) and ICGC (P = 0.004) cohorts. Tumor infiltration of CD8 T (P = 0.005) cells and naïve B cells (P = 0.001) was greater in the low-risk than in the high-risk group, with infiltration of these cells negatively correlated with risk score. Moreover, the TMB score was lower in the low-risk than in the high-risk group (P = 0.0051). Importantly, patients in low-risk group had better immunotherapy responses than in the high-risk group in an independent immunotherapy cohort (IMvigor210) (P = 0.039). The CAV1 and SOD3 were highly expressed in CAFs of PAAD tissues, which revealed by immunohistochemical staining. In summary, this comprehensive analysis resulted in the development of a novel prognostic signature, which was associated with immune cell infiltration, drug sensitivity, and TMB, and could predict the prognosis and immunotherapy response of patients with PAAD.

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Fibroblast heterogeneity in pancreatic ductal adenocarcinoma: Perspectives in immunotherapy

Cited by 9 publications

References 101 publications

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

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

Systematic analysis of expression profiles and prognostic significance of the FGF gene family in pancreatic adenocarcinoma

Cancer-associated fibroblast-related prognostic signature predicts prognosis and immunotherapy response in pancreatic adenocarcinoma based on single-cell and bulk RNA-sequencing

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