RETRACTED: Dual targeting of TGF-β and PD-L1 inhibits tumor growth in TGF-β/PD-L1-driven colorectal carcinoma

Khalili-Tanha, Ghazaleh; Fiuji, Hamid; Gharib, Masoumeh; Moghbeli, Meysam; Khalili-Tanha, Nima; Rahmani, Farzad; Shakour, Neda; Maftooh, Mina; Hassanian, Seyed Mahdi; Asgharzadeh, Fereshteh; Shahidsales, Soodabeh; Anvari, Kazem; Mozafari, M. R.; Ferns, Gordon A.; Batra, Jyotsna; Giovannetti, Elisa; Rezayi, Majid; Avan, Amir

doi:10.1016/j.lfs.2023.121865

Cited by 12 publications

(4 citation statements)

References 46 publications

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“…The combination scheme based on PD-1/PD-L1 antibodies is expected to address the shortcomings of low efficiency and susceptibility to drug resistance in a single target, making it a frontier in international research ( 47 ). With further research on the mechanism of signaling pathways of PD-1/PD-L1 and TGFR2/TGF- β in tumors, bifunctional anti-PD-L1/TGF-βRII agents have shown that it can simultaneously block PD-1/PD-L1 and TGFR2/TGF-β signal pathway, promote the activation of effector T cells, regulate the tumor microenvironment, reverse immunosuppression and fibrosis, and show better anti-tumor effect than PD-L1 monoclonal antibody in a variety of mouse tumor-bearing models ( 48 ). The bifunctional agent bintrafusp alfa (previously named M7824), comprising the extracellular domain of human TGFβRII (TGFβ Trap) linked to the C-terminus of the human anti-PD-L1 heavy chain (αPD-L1), has been developed in an attempt to address this issue ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a meta-analysis based on mixed-effect models

Zheng,

Deng,

Huang

et al. 2023

Front. Med.

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BackgroundExtensive-stage small cell lung cancer (ES-SCLC) is a highly invasive and fatal disease with limited therapeutic options and poor prognosis. Our study aims to systematically evaluate the efficacy and safety of immune checkpoint inhibitors combined with chemotherapy (ICIs+ChT) vs. chemotherapy alone (ChT) in the first-line treatment of ES-SCLC.MethodsA literature search was performed for randomized controlled trials (RCTs) related to “ICIs+ChT” vs. “ChT” in the first-line treatment of ES-SCLC in PubMed, Cochrane Library, Embase, CNKI, and other databases. RevMan 5.4 software was used to perform meta-analyses with hazard ratio (HR) and relative risk (RR). SAS 9.4 software was applied to conduct a mixed-effect model meta-analysis of the survival outcomes and draw survival curves.ResultsA total of 2,638 patients with ES-SCLC from 6 RCTs were included, of which 1,341 patients received “ICIs+ChT” and 1,297 received ChT. Based on the meta-analysis results provided by the mixed-effect model, patients receiving the “ICIs+ChT” regimen had a significantly longer overall survival (OS, HR = 0.800, 95% CI = 0.731–0.876, P < 0.001) and progression-free survival (PFS, HR = 0.815, 95% CI = 0.757–0.878, P <0.001) in comparison to those receiving ChT only. Compared with ChT, “ICIs+ChT” did neither improve the objective response rate (ORR, RR = 1.06, 95% CI = 1.00–1.12, P = 0.06) nor did it improve the disease control rate (DCR, RR = 0.97, 95% CI = 0.92–1.03, P = 0.35). Although the incidence of grade 3 to 5 treatment-related adverse events (trAEs) in the “ICIs+ChT” subgroup did not increase (RR = 1.16, 95% CI = 0.97–1.39, P = 0.11), the incidence of grade 3 to 5 immune-related adverse events (irAEs) increased significantly (RR = 4.29, 95% CI = 1.73–10.61, P < 0.00001).ConclusionICIs+ChT regimen could significantly prolong OS and PFS in patients with ES-SCLC compared with ChT alone. Although the incidence of irAEs in “ICIs+ChT” is higher than that in the “ChT” subgroup, the incidence of trAEs is similar within the two subgroups. ICIs combined with chemotherapy demonstrated a good choice as first-line treatment for ES-SCLC.Systematic review registrationPROSPERO, identifier: CRD42022348496.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a meta-analysis based on mixed-effect models

Zheng,

Deng,

Huang

et al. 2023

Front. Med.

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“…In addition, TGF-β regulates B cell development and function for autoimmunity, that hematopoiesis stem cells are under high pressure of TGF-β in fetal liver and bone marrow [217]. Inhibiting of TGF-β suppresses the fibrosis in CRC [218,219].…”

Section: Tgfβ Mediated Signaling Pathwaysmentioning

confidence: 99%

Signaling pathways in colorectal cancer: implications for the target therapies

Song,

Chen,

Wei

et al. 2024

Mol Biomed

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Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.

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“…PD-L1 upregulation is found to be more common in mCRC ( 23 ), and PD-L1 expression assists tumor cells in evading immune surveillance by enhancing Treg function. PD-L1 expressed on tumor cells binds with the PD-1 receptor on activated T cells, inhibiting cytotoxic T cells ( 24 ). PD-L1 expression is significantly upregulated in tumor tissues via various mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…PD-L1 expression is significantly upregulated in tumor tissues via various mechanisms. Interestingly, a positive correlation between the expression of TGF-β and PD-L1 has been observed in CRC ( 24 ). This highlights the need for a dual-targeting strategy to regulate the inhibitory effect of immune checkpoints displayed by PD-L1 and TGF-β pathways in CRC.…”

Section: Introductionmentioning

confidence: 99%

Withametelin inhibits TGF-β induced Epithelial-to-Mesenchymal Transition and Programmed-Death Ligand-1 expression in vitro

Fathima,

Farboodniay Jahromi,

Begum

et al. 2024

Front. Oncol.

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Withanolides are a group of naturally occurring plant-based small molecules known for their wide range of host cellular functions. The anticancer potential of withanolides has been explored in varying cancer cell lines in vitro. Based on our prior studies, among the tested withanolides, withametelin (WM) has shown significant cytotoxicity with the highest efficacy on HCT-116 colon cancer cells (IC50 0.719 ± 0.12μM). Treatment with WM reduced the TGF-β driven proliferation, colony-forming ability, migration, and invasiveness of HCT-116 cells in vitro. WM also downregulated the expression of mesenchymal markers such as N-CADHERIN, SNAIL, and SLUG in HCT-116 cells. At the molecular level, WM inhibited TGF-β induced phosphorylation of SMAD2/3 and reduced the expression of an immune checkpoint inhibitor programmed-death ligand-1 (PD-L1). Our study highlights the possible anticancer mechanisms of WM involving modulation of the TGF-β pathway and associated target gene expression, suggesting its potential utility in cancer therapy.

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RETRACTED: Dual targeting of TGF-β and PD-L1 inhibits tumor growth in TGF-β/PD-L1-driven colorectal carcinoma

Cited by 12 publications

References 46 publications

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a meta-analysis based on mixed-effect models

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a meta-analysis based on mixed-effect models

Signaling pathways in colorectal cancer: implications for the target therapies

Withametelin inhibits TGF-β induced Epithelial-to-Mesenchymal Transition and Programmed-Death Ligand-1 expression in vitro

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