Co-inhibition of the TGF-β pathway and the PD-L1 checkpoint by pH-responsive clustered nanoparticles for pancreatic cancer microenvironment regulation and anti-tumor immunotherapy

Wang, Yang; Gao, Zhuxin; Du, Xiao-Jiao; Chen, Senbiao; Zhang, Wangcheng; Wang, Jilong; Li, Hongjun; He, Xinyu; Cao, Jie; Wang, Jun

doi:10.1039/d0bm00916d

Cited by 53 publications

(36 citation statements)

References 44 publications

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“…282 Researchers designed pH-responsive clustered nanoparticles that can deliver TβRI kinase inhibitor galunisertib (LY2157299) and small interfering RNA targeting PD-L1 to the PDAC stroma microenvironment, and this regimen showed significant antitumor efficiency by both provoking antitumor immunity and suppressing tumor growth in PDAC mouse models. 283 However, despite these highly encouraging results mentioned above, we like to provide a note of caution as different tumor models with different immunogenicity can exhibit totally different, sometimes even opposite, results. 284 Some therapies in which anti-TGFβ and immunotherapy are combined have entered clinical evaluations with patients ( Table 1).…”

Section: Targeting Tgfβ In Cancer Therapy: Challenges and Opportunitiesmentioning

confidence: 93%

Targeting TGFβ signal transduction for cancer therapy

Liu

Ren

Dijke

2021

Sig Transduct Target Ther

204

158

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Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

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Section: Targeting Tgfβ In Cancer Therapy: Challenges and Opportunitiesmentioning

confidence: 93%

Targeting TGFβ signal transduction for cancer therapy

Liu

Ren

Dijke

2021

Sig Transduct Target Ther

204

158

View full text Add to dashboard Cite

show abstract

“…extracellular pH (PHe)-responsive clustered nanoparticles to deliver drugs in a mouse model (Wang et al, 2020). Wiley et al (2018) found that CAFs increased the expression of GPR68 (a G-protein-coupled receptor), which could sense acidic environments to further increase fibrosis and IL-6 levels, leading to the development of PDAC proliferation.…”

Section: Target the Acidic Microenvironment Or Ecm Remodelingmentioning

confidence: 99%

Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer

Geng

Chen

Zhao

et al. 2021

Front. Cell Dev. Biol.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA)high interleukin-6 (IL-6)low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMAlow IL-6high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.

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“…In addition, we have identified markers, pathways and upstream regulators putatively associated with cumulative oxygen utilization. The pathway most closely associated with oxygen utilization involves several TGFB signaling genes (epithelial-mesenchymal transition pathway), which is important for helping to diminish CD8+ T cell activation (28)(29)(30)(31)(32). Additional pathways involved with T cell activation (e.g., T cell receptor signaling) and differentiation (e.g., IL-12 signaling).…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia

et al. 2021

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Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO, and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.

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Co-inhibition of the TGF-β pathway and the PD-L1 checkpoint by pH-responsive clustered nanoparticles for pancreatic cancer microenvironment regulation and anti-tumor immunotherapy

Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dense extracellular matrix (ECM) surrounding tumor cells to sequester CD8+ T cell infiltration and prevent drug penetration. Concomitant inhibition of both TGF-β pathway and...

Cited by 53 publications

References 44 publications

Targeting TGFβ signal transduction for cancer therapy

Targeting TGFβ signal transduction for cancer therapy

Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer

Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia

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