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.

scholarly journals Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

2021 ◽  
Vol 22 (4) ◽  
pp. 2091
Author(s):  
Yu-Hung Lee ◽  
Ching-Fang Yu ◽  
Ying-Chieh Yang ◽  
Ji-Hong Hong ◽  
Chi-Shiun Chiang
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Pancreatic Tumor ◽  
Tumor Model ◽  
Suppressor Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Control Group ◽  
Myeloid Derived Suppressor Cell

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.

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 Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huapan Fang ◽  
Zhaopei Guo ◽  
Jie Chen ◽  
Lin Lin ◽  
Yingying Hu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Epigenetic Regulation ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Memory ◽  
Escape Mechanism ◽  
Immune Escape Mechanism

AbstractImmunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.

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 Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

2020 ◽  
Author(s):  
Michele Bortolomeazzi ◽  
Mohamed Reda Keddar ◽  
Lucia Montorsi ◽  
Amelia Acha-Sagredo ◽  
Lorena Benedetti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Critical Threshold ◽  
Mutational Burden ◽  
Antigen Presenting

To dissect the determinants of the heterogeneous response of colorectal cancer (CRC) to immune checkpoint blockade, we profile tumour and immune infiltrates of 721 cancer regions from 29 patients treated with Pembrolizumab or Nivolumab. Combining multi-regional whole exome, RNA and T-cell receptor sequencing we show that anti-PD1 agents are most effective in CRCs with high mutational burden and low activation of the WNT pathway. However, above a critical threshold defining the hypermutated phenotype, response is no longer associated with mutational burden but rather with high clonality of immunogenic mutations, expanded T cells and active immune escape mechanisms. Using high-dimensional imaging mass cytometry and multiplexed immunofluorescence, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 infiltrates interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting their expansion in intra-tumour niches.

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