scholarly journals Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway

2020 ◽  
Vol 21 (21) ◽  
pp. 8035
Author(s):  
Yang Yang ◽  
Nhi Huynh ◽  
Chelsea Dumesny ◽  
Kai Wang ◽  
Hong He ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Pancreatic Stellate Cells ◽  
Inhibitory Effects ◽  
Anti Cancer ◽  
Pancreatic Tumour ◽  
Mouse Study

The anti-cancer effects of cannabinoids including CBD (Cannabidiol) and THC ((−)-trans-∆9-tetrahydrocannabinol) have been reported in the case of pancreatic cancer (PC). The connection of these cannabinoids to KRas oncogenes that mutate in more than 90% of PC, and their effects on PD-L1, a key target of immune checkpoint blockade, have not been thoroughly investigated. Using cell lines and mouse models of PC, the effects of CBD and THC on cancer growth, the interaction between PC cells and a stromal cell, namely pancreatic stellate cells (PSCs), and the mechanism(s) involved were determined by cell-based assays and mouse study in vivo. CBD and THC inhibited the proliferation of PC, PSC, and PSC-stimulated PC cells. They also suppressed pancreatic tumour growth in mice. Furthermore, CBD and/or THC reduced the expression of PD-L1 by either PC or PSC cells. Knockout of p-21 activated kinase 1 (PAK1, activated by KRas) in PC and PSC cells and, in mice, dramatically decreased or blocked these inhibitory effects of CBD and/or THC. These results indicated that CBD and THC exerted their inhibitions on PC and PSC via a p-21 activated kinase 1 (PAK1)-dependent pathway, suggesting that CBD and THC suppress Kras activated pathway by targeting PAK1. The inhibition by CBD and THC of PD-L1 expression will enhance the immune checkpoint blockade of PC.

scholarly journals Sequential targeting of PI3Kδ and LAG3 as an effective anti-cancer approach

2021 ◽  
Author(s):  
Sarah N. Lauder ◽  
Bart Vanhaesebroeck ◽  
Awen Gallimore
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Solid Tumours ◽  
Checkpoint Blockade ◽  
Tumour Control ◽  
Anti Cancer ◽  
Clinical Models

SummaryEmerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling successful tumour control in all treated mice.

scholarly journals Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

2021 ◽  
Vol 15 ◽  
pp. 117955492110355
Author(s):  
Tianhang Li ◽  
Tianyao Liu ◽  
Wenjie Zhu ◽  
Shangxun Xie ◽  
Zihan Zhao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Escape ◽  
Suppressor Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Great Promise ◽  
Therapy Process ◽  
Myeloid Derived Suppressor Cell ◽  
Anti Cancer ◽  
Immune Suppressor

Immune-checkpoint blockade (ICB) demonstrated inspiring effect and great promise in anti-cancer therapy. However, many obstacles, such as drug resistance and difficulty in patient selection, limited the efficacy of ICB therapy and awaited to be overcome. By timely identification and intervention of the key immune-suppressive promotors in the tumor microenvironment (TME), we may better understand the mechanisms of cancer immune-escape and use novel strategies to enhance the therapeutic effect of ICB. Myeloid-derived suppressor cell (MDSC) is recognized as a major immune suppressor in the TME. In this review, we summarized the roles MDSC played in the cancer context, focusing on its negative biologic functions in ICB therapy, discussed the strategies targeted on MDSC to optimize the diagnosis and therapy process of ICB and improve the efficacy of ICB therapy against malignancies.

Abstract PO-017: Targeting NF-kB pathway through IRAK4 renders immune checkpoint blockade effective in pancreatic cancer

2020 ◽  
Author(s):  
Daoxiang Zhang ◽  
Vikas Somani ◽  
Paarth B. Dodhiawala ◽  
Patrick M. Grierson ◽  
Lin Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer and Improves Immune Checkpoint Blockade

2021 ◽  
Author(s):  
Nancy Danielle Ebelt ◽  
Vic Zamloot ◽  
Edith Zuniga ◽  
Kevin B Passi ◽  
Lukas J. Sobocinski ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Resistance ◽  
Collagen Deposition ◽  
Tumor Bearing ◽  
Bacterial Collagenase

Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.

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