scholarly journals Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jun Zhao ◽  
Xiaofei Wen ◽  
Li Tian ◽  
Tingting Li ◽  
Chunyu Xu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Irreversible Electroporation ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

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 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 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.

scholarly journals Semaphorin 4D Blockade Enhances T-Cell Penetration and Potentiates Response to Immune Checkpoint Blockade in a Murine Model of Pancreatic Cancer

2021 ◽  
Vol 233 (5) ◽  
pp. S252-S253
Author(s):  
Luis I. Ruffolo ◽  
Nicholas A. Ullman ◽  
Katherine M. Jackson ◽  
Paul R. Burchard ◽  
Ryan C. Fields ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
Murine Model ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Penetration ◽  
Semaphorin 4D

scholarly journals Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer

Open Biology ◽  
2021 ◽  
Vol 11 (11) ◽  
Author(s):  
Courtney T. Stump ◽  
Kevin Roehle ◽  
Nataly Manjarrez Orduno ◽  
Stephanie K. Dougan
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Stereotactic Body Radiation Therapy ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Growth Delay ◽  
T Cell Priming ◽  
Effects Of Radiation

Radiation has been a pillar of cancer therapy for decades. The effects of radiation on the anti-tumour immune response are variable across studies and have not been explicitly defined in poorly immunogenic tumour types. Here, we employed combination checkpoint blockade immunotherapy with stereotactic body radiation therapy and examined the effect on tumour growth and immune infiltrates in subcutaneous and orthotopic mouse models of pancreatic cancer. Although immune checkpoint blockade and radiation were ineffective alone, their combination produced a modest growth delay in both irradiated and non-irradiated tumours that corresponded with significant increases in CD8+ T cells, CD4+ T cells and tumour-specific T cells as identified by IFNγ ELISpot. We conclude that radiation enhances priming of tumour-specific T cells in poorly immunogenic tumours and that the frequency of these T cells can be further increased by combination with immune checkpoint blockade.

scholarly journals Systemic Immune-Inflammation Index and Changes of Neutrophil-Lymphocyte Ratio as Prognostic Biomarkers for Patients With Pancreatic Cancer Treated With Immune Checkpoint Blockade

2021 ◽  
Vol 11 ◽  
Author(s):  
Jin Shang ◽  
Xiao Han ◽  
Haoran Zha ◽  
Haitao Tao ◽  
Xiaoyan Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Prognostic Significance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Prognostic Biomarkers ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Risk Of Death ◽  
Immune Inflammation

The efficacy of current treatment regimens for pancreatic cancer (PC) remains unsatisfactory. In recent years, immune checkpoint blockade (ICB) therapy has shown promising anti-tumor outcomes in many malignancies, including PC. Inexpensive and readily available biomarkers which predict therapeutic responses and prognosis are in critical need. Systemic immune-inflammation index (SII) and neutrophil-lymphocyte ratio (NLR) are emerging predictors for prognosis of various tumors. We aim to investigate the prognostic significance of baseline SII, NLR, and their changes in PC patients treated with ICB. Our retrospective analysis included PC patients treated with ICB therapy in the Chinese PLA General Hospital. All demographic, biological, and clinical data were extracted from medical records. Relative changes of SII after two doses of ICB were defined as ΔSII% and calculated as (SIIafter 2 doses-SIIbaseline)/SIIbaseline, and so was the case for ΔNLR%. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier curves. The prognostic significance of baseline SII, NLR, and their changes was assessed in univariate and multivariate analyses using the Cox proportional hazard regression model. In total, 122 patients with PC treated with ICB were included in the present analysis. Elevated baseline SII (HR=3.28; 95% CI:1.98–5.27; P=0.03) and ΔNLR% (HR=2.21; 95% CI:1.03–4.74; P=0.04) were significantly correlated with an increased risk of death. For PC patients receiving ICB combined with chemotherapies or radiotherapies as the first-line treatment, increased baseline SII was a negative predictor for both OS (HR=8.06; 95% CI:1.71–37.86; P=0.01) and PFS (HR=2.84; 95%CI:1.37–10.38; P=0.04). Our study reveals the prognostic value of baseline SII and NLR changes in PC patients receiving ICB therapy. The clinical utility of these prognostic biomarkers needs to be further studied in prospective studies.

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