The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges

Müller, Marie; Haghnejad, Vincent; Schaefer, Marion; Gauchotte, Guillaume; Caron, Bénédicte; Peyrin–Biroulet, Laurent; Bronowicki, Jean–Pierre; Neuzillet, Cindy; Lopez, Anthony

doi:10.3390/cancers14040995

Cited by 40 publications

(46 citation statements)

References 122 publications

(180 reference statements)

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“…S4B). The proportion of M1 macrophages, T cells, and antigen-presenting dendritic cells, known to be prognostically favorable in PDAC ( 51 ), was increased in gal 4–KD tumors ( Fig. 5C ).…”

Section: Resultsmentioning

confidence: 92%

Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer

Lidström

Cumming

Gaur

et al. 2022

Cancer Immunology Research

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell-produced protein that was deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments, we observed increased infiltration of T cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. By performing single-cell RNA-sequencing, we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression associated with a higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T cells, and antigen-presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation residues on CD3ε/δ. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC.

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Section: Resultsmentioning

confidence: 92%

Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer

Lidström

Cumming

Gaur

et al. 2022

Cancer Immunology Research

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“…At the same time, fibrosis exacerbates the lack of vascularity and hypoxia in TME, which not only promotes tumor proliferation, invasion, and migration but also makes it resistant to anti-tumor agents. In addition, the low infiltration of effector T cells and high infiltration of immune suppressor cells in the TME of most pancreatic cancers makes them exhibit an immune-desert phenotype, i.e., an immunosuppressive TME phenotype (Muller et al, 2022). In this process, CAFs can recruit immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and, through the induction of cytokines such as IL-6 and IL-11, and participate in tumor immune evasion mechanisms (Tang et al, 2012;Mace et al, 2013;Pothula et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Construction of a cancer-associated fibroblasts-related long non-coding RNA signature to predict prognosis and immune landscape in pancreatic adenocarcinoma

Zhao

et al. 2022

Front. Genet.

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Background: Cancer-associated fibroblasts (CAFs) are an essential cell population in the pancreatic cancer tumor microenvironment and are extensively involved in drug resistance and immune evasion mechanisms. Long non-coding RNAs (lncRNAs) are involved in pancreatic cancer evolution and regulate the biological behavior mediated by CAFs. However, there is a lack of understanding of the prognostic signatures of CAFs-associated lncRNAs in pancreatic cancer patients.Methods: Transcriptomic and clinical data for pancreatic adenocarcinoma (PAAD) and the corresponding mutation data were obtained from The Cancer Genome Atlas database. lncRNAs associated with CAFs were obtained using co-expression analysis. lncRNAs were screened by Cox regression analysis using least absolute shrinkage and selection operator (LASSO) algorithm for constructing predictive signature. According to the prognostic model, PAAD patients were divided into high-risk and low-risk groups. Kaplan-Meier analysis was used for survival validation of the model in the training and validation groups. Clinicopathological parameter correlation analysis, univariate and multivariate Cox regression, time-dependent receiver operating characteristic (ROC) curves, and nomogram were performed to evaluate the model. The gene set variation analysis (GSVA) and gene ontology (GO) analyses were used to explore differences in the biological behavior of the risk groups. Furthermore, single-sample gene set enrichment analysis (ssGSEA), tumor mutation burden (TMB), ESTIMATE algorithm, and a series of immune correlation analyses were performed to investigate the relationship between predictive signature and the tumor immune microenvironment and screen for potential responders to immune checkpoint inhibitors. Finally, drug sensitivity analyses were used to explore potentially effective drugs in high- and low-risk groups.Results: The signature was constructed with seven CAFs-related lncRNAs (AP005233.2, AC090114.2, DCST1-AS1, AC092171.5, AC002401.4, AC025048.4, and CASC8) that independently predicted the prognosis of PAAD patients. Additionally, the high-risk group of the model had higher TMB levels than the low-risk group. Immune correlation analysis showed that most immune cells, including CD8+ T cells, were negatively correlated with the model risk scores. ssGSEA and ESTIMATE analyses further indicated that the low-risk group had a higher status of immune cell infiltration. Meanwhile, the mRNA of most immune checkpoint genes, including PD1 and CTLA4, were highly expressed in the low-risk group, suggesting that this population may be “hot immune tumors” and have a higher sensitivity to immune checkpoint inhibitors (ICIs). Finally, the predicted half-maximal inhibitory concentrations of some chemical and targeted drugs differ between high- and low-risk groups, providing a basis for treatment selection.Conclusion: Our findings provide promising insights into lncRNAs associated with CAFs in PAAD and provide a personalized tool for predicting patient prognosis and immune microenvironmental landscape.

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“…The most prevalent form of this cancer is the exocrine pancreatic ductal adenocarcinoma (PDAC) ( 131 ), which is among the most aggressive solid tumors due to the highly immunosuppressive TME and poor response to chemotherapy, radiotherapy and immunotherapy. This poor treatment response may in part be explained by the dense desmoplastic stroma and the abundance of immunosuppressive cells in the PDAC TME, which excludes antitumoral T cells, resulting in a cold tumor ( 132 , 133 ). Radiation can, therefore, be beneficial in boosting the immune system’s response to systemic therapies and in achieving tumor regression by altering the TME ( 134 , 135 ).…”

Section: Immune Landscape and Radiotherapymentioning

confidence: 99%

The current understanding of the immune landscape relative to radiotherapy across tumor types

et al. 2023

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Radiotherapy is part of the standard of care treatment for a great majority of cancer patients. As a result of radiation, both tumor cells and the environment around them are affected directly by radiation, which mainly primes but also might limit the immune response. Multiple immune factors play a role in cancer progression and response to radiotherapy, including the immune tumor microenvironment and systemic immunity referred to as the immune landscape. A heterogeneous tumor microenvironment and the varying patient characteristics complicate the dynamic relationship between radiotherapy and this immune landscape. In this review, we will present the current overview of the immunological landscape in relation to radiotherapy in order to provide insight and encourage research to further improve cancer treatment. An investigation into the impact of radiation therapy on the immune landscape showed in several cancers a common pattern of immunological responses after radiation. Radiation leads to an upsurge in infiltrating T lymphocytes and the expression of programmed death ligand 1 (PD-L1) which can hint at a benefit for the patient when combined with immunotherapy. In spite of this, lymphopenia in the tumor microenvironment of ‘cold’ tumors or caused by radiation is considered to be an important obstacle to the patient’s survival. In several cancers, a rise in the immunosuppressive populations is seen after radiation, mainly pro-tumoral M2 macrophages and myeloid-derived suppressor cells (MDSCs). As a final point, we will highlight how the radiation parameters themselves can influence the immune system and, therefore, be exploited to the advantage of the patient.

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The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges

Cited by 40 publications

References 122 publications

Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer

Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer

Construction of a cancer-associated fibroblasts-related long non-coding RNA signature to predict prognosis and immune landscape in pancreatic adenocarcinoma

The current understanding of the immune landscape relative to radiotherapy across tumor types

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