PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer

Yaghoubi, Neda; Soltani, Arash; Ghazvini, Kiarash; Hassanian, Seyed Mahdi

doi:10.1016/j.biopha.2018.11.105

Cited by 227 publications

(149 citation statements)

References 79 publications

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“…Although the survival of colorectal cancer patients has significantly progressed over the past decades, prognosis of patients remains poor, with 5-year overall survival rates of 10% to 15% (27). Additionally, recent studies have indicated that immunosuppression is involved in oncogenicity, as well as tumor development and invasion in colorectal cancer (28,29). The present study clarified the specific mechanism of the promotion of colorectal cancer tumorigenesis and metastasis by lncRNA MIR17HG, and we propose that it may serve as a promising immunotherapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p

et al. 2019

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Immune dysregulation plays a vital role in colorectal cancer initiation and progression. Long noncoding RNAs (lncRNA) exhibit multiple functions including regulation of gene expression. Here, we identified an immune-related lncRNA, MIR17HG, whose expression was gradually upregulated in adjacent, adenoma, and colorectal cancer tissue. MIR17HG promoted tumorigenesis and metastasis in colorectal cancer cells both in vitro and in vivo. Mechanistically, MIR17HG increased the expression of NF-kB/RELA by competitively sponging the microRNA miR-375. In addition, RELA transcriptionally activated MIR17HG in a positive feedback loop by directly binding to its promoter region. Moreover, miR-17-5p, one of the transcribed miRNAs from MIR17HG, reduced the expression of the tumor suppressor B-cell linker (BLNK), resulting in increased migration and invasion of colorectal cancer cells. MIR17HG also upregulated PD-L1, indicating its potential role in immunotherapy. Overall, these findings demonstrate that MIR17HG plays an oncogenic role in colorectal cancer and may serve as a promising therapeutic target. Significance: These findings provide mechanistic insight into the role of the lncRNA MIR17HG and its miRNA members in regulating colorectal cancer carcinogenesis and progression.

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Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p

et al. 2019

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“…Therefore, therapy that targets the PD‐1/PD‐L1 signaling pathway has become a promising approach for T cell‐based oncotherapy (Feng et al, ; Topalian, Drake, & Pardoll, ). Anti‐PD1 antibodies (e.g., Opdivo) and anti‐PD‐L1 antibodies (e.g., Tecentriq) have demonstrated considerable therapeutic effect in clinical trials (Ellis et al, ; Yaghoubi, Soltani, Ghazvini, Hassanian, & Hashemy, ). However, side effects have also been observed in several cases because of antibody off‐target binding to normal tissues that express PD‐1 (or PD‐L1).…”

Section: Introductionmentioning

confidence: 99%

Stimuli‐responsive nanoparticles for the codelivery of chemotherapeutic agents doxorubicin and siPD‐L1 to enhance the antitumor effect

et al. 2019

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Cancer cells have been reported to exhibit high resistance against immune system recognition through various cell intrinsic and extrinsic mechanisms. Considerable challenges have been encountered in monotherapy with chemotherapeutics to attain the desired antitumor efficacy. In this study, a nanodelivery system was designed to incorporate doxorubicin (DOX) and programmed death‐ligand 1 (PD‐L1) small interfering RNA (siRNA), that is, siPD‐L1. DOX and siPD‐L1 were formed from a stimuli‐responsive polymer with a poly‐L‐lysine–lipoic acid reduction‐sensitive core and a tumor extracellular pH‐stimulated shedding polyethylene glycol layer. The codelivery system was stable under physiological pH conditions and demonstrated enhanced cellular uptake at the tumor site. Moreover, the combined treatment of DOX and siPD‐L1 exhibited improved antitumor effect in vitro and in vivo compared with either modality alone. The combination of chemotherapy and immunotherapy presented in this work through the codelivery of a chemotherapeutic agent and a gene‐silencing agent (siRNA) may provide a new strategy for cancer treatment.

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“…Not only can they exert cytotoxic effects on cancer cells (via infection, replication and release of viral progeny), but they simultaneously cause activation and proliferation of hitherto dormant immune cells in the TME. This provides a much-needed "jump start" for the immune system, allowing it to recognize and destroy cancer cells, including those which have acquired the ability to thwart host immunity (e.g., through expression of PD-L1, IL-23 and IL-10 receptors resulting in T cell exhaustion [14,15]).…”

Section: Discussionmentioning

confidence: 99%

Immune Characterization of Metastatic Colorectal Cancer Patients Post Reovirus Administration

Parakrama

Fogel

Chandy

et al. 2020

Preprint

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Background: KRAS mutations are prevalent in 40-45% of patients with colorectal cancer (CRC) and targeting this gene has remained elusive. Viruses are well known immune sensitizing agents. The therapeutic efficacy of oncolytic reovirus in combination with chemotherapy is underway in a phase 1 study of metastatic CRC. This study evaluates the nature of immune response by determining the cytokine expression pattern in peripheral circulation along with the distribution of antigen presenting cells (APCs) and activated T lymphocytes. Further the study evaluates the alterations in exosomal and cellular microRNA levels along with the effect of reovirus on leukocyte transcriptome.Methods: Reovirus was administered as a 60-minute intravenous infusion for 5 consecutive days every 28 days, at a tissue culture infective dose (TCID50) of 3x1010. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood prior to reovirus administration and post-reovirus on days 2, 8, and 15. The expression profile of 25 cytokines in plasma was assessed (post PBMC isolation) on an EMD Millipore multiplex Luminex platform. Exosome and cellular levels of miR-29a-3p was determined in pre and post reovirus treated samples. Peripheral blood mononuclear cells were stained with fluorophore labelled antibodies against CD4, CD8, CD56, CD70, and CD123, fixed and evaluated by flow cytometry. The expression of granzyme B was determined on core biopsy of one patient. Finally, Clariom D Assay, was used to determine the expression of 847 immune-related genes when compared to pre reovirus treatment by RNA sequencing analysis. A change was considered if the expression level either doubled or halved and the significance was determined at a p value of 0.001.Results:Cytokine assay indicated upregulation at day 8 for IL-12p40 (2.95; p=0.05); day 15 for GM-CSF (3.56; p=0.009), IFN-Ƴ (1.86; p=0.0004) and IL-12p70 (2.42; p=0.02). An overall reduction in IL-8, VEGF and RANTES/CCL5 was observed over the 15-day period. Statistically significant reductions were observed at Day 15 for IL-8 (0.457-fold, 53.3% reduction; p=0.03) and RANTES/CC5 (0.524-fold, 47.6% reduction; p=0.003). An overall increase in IL-6 was observed, with statistical significance at day 8 (1.98- fold; 98% increase, p=0.00007). APCs were stimulated within 48 hours and activated (CD8+ CD70+) T cells within 168 hours as determine by flow cytometry. Sustained reductions in exosomal and cellular levels of miR-29a-3p (a microRNA upregulated in CRC and associated with decreased expression of the tumor suppressor WWOX gene) was documented. Reovirus administration further resulted in increases in KRAS (33x) , IFNAR1 (20x), STAT3(5x), and TAP1 (4x) genes after 2 days; FGCR2A (23x) and CD244 (3x) after 8 days; KLRD1 (14x), TAP1 (2x) and CD244(2x) after 15 days. Reductions (>0.5x) were observed in VEGFA (2x) after 2 days; CXCR2 (2x), ITGAM (3x) after 15 days.Conclusions: Reovirus has profound immunomodulatory properties that span the genomic, protein and immune cell distribution levels. This is the first study with reovirus in cancer patients that demonstrates these multi- layered effects, demonstrating how reovirus can function as an immune stimulant (augmenting the efficacy of immuno-chemo-therapeutic drugs), and an oncolytic agent. Reovirus thus functions bimodally as an oncolytic agent causing lysis of tumor cells, and facilitator of immune-mediated recognition and destruction of tumor cells.

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PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer

Cited by 227 publications

References 79 publications

Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p

Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p

Stimuli‐responsive nanoparticles for the codelivery of chemotherapeutic agents doxorubicin and siPD‐L1 to enhance the antitumor effect

Immune Characterization of Metastatic Colorectal Cancer Patients Post Reovirus Administration

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