Dynamic profiling of immune microenvironment during pancreatic cancer development suggests early intervention and combination strategy of immunotherapy

Yang, Jiaqi; Zhang, Qi; Wang, Junli; Lou, Yiting; Hong, Zhengtao; Wei, Shumei; Sun, Ke; Wang, Jianbo; Chen, Yiwen; Sheng, Jianpeng; Su, Wei; Bai, Xueli; Liang, Tingbo

doi:10.1016/j.ebiom.2022.103958

Cited by 24 publications

(27 citation statements)

References 48 publications

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“…Since tumor cells are attacked by the body's immune system, the immune system within tumor tissue may be more active than that of normal tumor tissue (33). This may be a reason why the expression levels of the immune-related proteins STAT1 and BST2 are higher in OSCC than in normal tissues (34)(35)(36)(37). Further in-depth research on STAT1 and BST2 in tumor immunity is required.…”

Section: Discussionmentioning

confidence: 99%

BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway

Shan

Shen

Wang³

et al. 2023

Int J Oncol

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Oral squamous cell carcinoma (OSCC) is one of the main types of head and neck squamous cell carcinoma. Although progress has been made in treating OSCC, it remains a threat to human health, and novel therapeutic strategies are needed to extend the lifespan of patients with OSCC. The present study, evaluated whether bone marrow stromal antigen 2 (BST2) and STAT1 were potential therapeutic targets in OSCC. Small interfering RNA (siRNA) or overexpression plasmids were used to regulate BST2 or STAT1 expression. Western blotting and reverse transcription-quantitative PCR were performed to assess changes in the protein and mRNA expression levels of signaling pathway components. The effects of BST2 and STAT1 expression changes on the migration, invasion and proliferation of OSCC cells were assessed using the scratch test assay, Transwell assay and colony formation assay in vitro, respectively. Cell-derived xenograft models were used to evaluate the impact of BST2 and STAT1 on the occurrence and development of OSCC in vivo. Finally, it was demonstrated that BST2 expression was significantly upregulated in OSCC. Furthermore, it was demonstrated that high expression of BST2 in OSCC contributed to the metastasis, invasion and proliferation of OSCC cells. Moreover, it was demonstrated that the promoter region of BST2 was regulated by the transcription factor STAT1, and that the STAT1/BST2 axis could affect the behavior of OSCC via the AKT/ERK1/2 signaling pathway. In vivo studies also demonstrated that STAT1 downregulation inhibited OSCC growth by down-regulating BST2 expression via the AKT/ERK1/2 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway

Shan

Shen

Wang³

et al. 2023

Int J Oncol

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“…In this regard, we are evaluating the effects of inhibiting uPA in a clinically representative orthotopic mouse model (early and advanced) of PDAC in both immune-deficient and immune-competent (syngeneic KPC model, where a mixture of mouse cancer cells and mouse pancreatic stellate cells is implanted into the KPC mouse pancreas) settings with more numbers of mice. The immune cell landscape in this model closely resembles that of human pancreatic cancer with infiltration of myeloid-derived suppressor cells (MDSC), Treg cells and a few CD8+ cytotoxic T cells (141)(142)(143). Future work will also combine inhibition with multiagent chemotherapy to further optimise outcomes or to demonstrate that single-agent chemotherapy + targeted therapy may be preferred to current multiagent strategies in selected patients.…”

Section: Discussionmentioning

confidence: 99%

Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU)

Hosen

Uddin²,

Xu³

et al. 2022

Front. Immunol.

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BackgroundPrevious studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition.MethodsThis study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis.ResultsOur analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis.ConclusionElevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU.

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“…Naïve B cells, which appeared in stage II but not stage I, gradually repolarize to those with pro-tumor or anti-tumor function in stage III [11]. Immature Ly-6C+ monocytes repolarize from a BST2+/MHC-II + phenotype to an Arg-1 + phenotype over time [12].…”

Section: Introductionmentioning

confidence: 99%

“…The tumor microenvironment (TME) of pancreatic cancer, mainly comprising cancer cells, cancer-associated fibroblasts (CAFs), and immune cells, is dynamic during natural tumor progression and chemotherapeutic treatment (Figure 1) [10][11][12]. The number of ductal cells gradually decreased with tumor stage (I-II-III) progression (44.88%-36.04%-18.95%) [11].…”

Section: Introductionmentioning

confidence: 99%

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

Peng

Ying

Zhang

et al. 2023

Cancers

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The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.

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Dynamic profiling of immune microenvironment during pancreatic cancer development suggests early intervention and combination strategy of immunotherapy

Cited by 24 publications

References 48 publications

BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway

BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway

Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU)

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

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