Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Cedra, Susan; Wiegand, Susanne; Kolb, Marlen; Dietz, Andreas; Wichmann, Gunnar

doi:10.3390/cancers9090117

Cited by 6 publications

(3 citation statements)

References 22 publications

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“…Some reasons for the unexpected clinical low efficacy in glioblastoma could be related to the fast off-rate of cilengitide from its targets, the rapid plasma clearance, or the poor perfusion of the brain tumor environment (43). However, it is important to note that a beneficial therapeutic action was found when administered in association with standard radiotherapy or chemotherapy (125, 126), and this was also found in other type of tumors (127, 128).…”

Section: Thyroid Hormone Non-genomic Actions In T Cell Lymphomasmentioning

confidence: 99%

Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

et al. 2019

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T-cell lymphomas (TCL) are a heterogeneous group of aggressive clinical lymphoproliferative disorders with considerable clinical, morphological, immunophenotypic, and genetic variation, including ~10–15% of all lymphoid neoplasms. Several evidences indicate an important role of the non-neoplastic microenvironment in promoting both tumor growth and dissemination in T cell malignancies. Thus, dysregulation of integrin expression and activity is associated with TCL survival and proliferation. We found that thyroid hormones acting via the integrin αvβ3 receptor are crucial factors in tumor microenvironment (TME) affecting the pathophysiology of TCL cells. Specifically, TH-activated αvβ3 integrin signaling promoted TCL proliferation and induced and an angiogenic program via the up-regulation of the vascular endothelial growth factor (VEGF). This was observed both on different TCL cell lines representing the different subtypes of human hematological malignancy, and in preclinical models of TCL tumors xenotransplanted in immunodeficient mice as well. Moreover, development of solid tumors by inoculation of murine TCLs in syngeneic hyperthyroid mice, showed increased tumor growth along with increased expression of cell cycle regulators. The genomic or pharmacological inhibition of integrin αvβ3 decreased VEGF production, induced TCL cell death and decreased in vivo tumor growth and angiogenesis. Here, we review the non-genomic actions of THs on TCL regulation and their contribution to TCL development and evolution. These actions not only provide novel new insights on the endocrine modulation of TCL, but also provide a potential molecular target for its treatment.

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Section: Thyroid Hormone Non-genomic Actions In T Cell Lymphomasmentioning

confidence: 99%

Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

et al. 2019

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“…First, we evaluated the effect of multiple cytokines on inducing PD-L2 expression, including epidermal growth factor (EGF), IL-8, IL-10, tumor necrosis factor (TNF-α), IL-6, which were correlated with the response to cetux treatment in HNSCC. [21][22][23][24] Among them, EGF significantly upregulated PD-L2 levels compared with other cytokines (online supplemental figure 4A). Furthermore, PD-L2 WT protein expression level was increased in response to EGF stimulation, whereas non-glycosylated PD-L2 4NQ mutant expression was not affected by EGF (online supplemental figure 4B).…”

Section: Egf/stat3 Signaling Drives Pd-l2 Glycosylation Through N-glycotransferase Fut8mentioning

confidence: 99%

PD-L2 glycosylation promotes immune evasion and predicts anti-EGFR efficacy

Gao

et al. 2021

J Immunother Cancer

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BackgroundCombination therapy has been explored for advanced head and neck squamous cell carcinoma (HNSCC) owing to the limited efficacy of anti-epidermal growth factor receptor (EGFR) therapy. Increased expression and glycosylation of immune checkpoint molecules in tumors are responsible for cetuximab therapy refractoriness. The role of programmed death ligand 2 (PD-L2), a ligand of PD-1, in the immune function is unclear. Here, we examined the regulatory mechanism of PD-L2 glycosylation and its role in antitumor immunity and cetuximab therapy.MethodsSingle-cell RNA sequencing and immunohistochemical staining were used to investigate PD-L2 expression in cetuximab-resistant/sensitive HNSCC tissues. The mechanism of PD-L2 glycosylation regulation was explored in vitro. The effects of PD-L2 glycosylation on immune evasion and cetuximab efficacy were verified in vitro and using mice bearing orthotopic SCC7 tumors.ResultsThe PD-L2 levels were elevated and N-glycosylated in patients with cetuximab-resistant HNSCC. Glycosylated PD-L2 formed a complex with EGFR, which resulted in the activation of EGFR/signal transducer and activator of transcription 3 (STAT3) signaling and decreased the cetuximab binding affinity to EGFR. The N-glycosyltransferase fucosyltransferase (FUT8), a transcriptional target of STAT3, was required for PD-L2 glycosylation. Moreover, glycosylation modification stabilized PD-L2 by blocking ubiquitin-dependent lysosomal degradation, which consequently promoted its binding to PD-1 and immune evasion. Inhibition of PD-L2 glycosylation using Stattic, a specific STAT3 inhibitor, or PD-L2 mutation blocking its binding to FUT8, increased cytotoxic T lymphocyte activity and augmented response to cetuximab.ConclusionsIncreased expression and glycosylation of PD-L2 in tumors are an important mechanism for cetuximab therapy refractoriness. Thus, the combination of PD-L2 glycosylation inhibition and cetuximab is a potential therapeutic strategy for cancer.

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“…To organize the current treatment options in clinical trials into clinically meaningful arms, we used general prespecified criteria, as shown in Table 1. Cilengitide (Cil) and cetuximab (Cet) are seldom used in NSCLC, and for statistical convenience and network simplification, Cil is categorized in the aVEGFR class, and Cet is categorized in the ET class [48].…”

Section: Definitions Of Outcomes and Treatment Armsmentioning

confidence: 99%

Therapeutic options for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer: a Bayesian network secondary analysis

Zeng

Wan

et al. 2020

Aging

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The most favorable treatments for advanced EGFR-mutant NSCLC are less indicated. Forty-one studies were eligible for this Bayesian network secondary analysis. For PFS, erlotinib (Erlo)+bevacizumab (Bev) (HR 0.26, 95% CrI: 0.08-0.75 vs placebo), osimertinib (Osi) (HR 0.29, 0.11-0.70 vs placebo), and afatinib (Afa) were topranking individual treatments, while immunotherapy (IT)+anti-VEGFR (aVEGFR)+platinum-based therapy (Plat) (HR 0.42, 0.06-2.63 vs placebo), EGFR-TKI (ET)+aVEGFR (HR 0.35, 0.14-0.85 vs placebo), and ET+aVEGFR+Plat were top-ranking medication classes. For OS, Osi (HR 0.52, 0.10-2.00 vs placebo), cetuximab (Cet)+Bev+Plat (HR 0.51, 0.06-3.38 vs placebo), and cilengitide (Cil)+Cet+Plat were top-ranking individual treatments, while ET+aVEGFR+Plat, ET+Plat, and third-generation EGFR-TKI (3rd ET) were top-ranking medication classes. For PFS regarding the EGFR genomic aberration status, Erlo+Bev, Osi, and Afa were superior for exon 19 deletion status, whereas ET+Bev, Osi, and gefitinib (Gef)+pemetrexed (Peme) were excellent for exon 21 L858Arg mutation status. The results were consistent in terms of the ORR and DoR and remained robust across sensitivity analyses. However, Erlo + Bev had the most grade 3 or higher adverse events. Osi, Erlo+Bev, and Erlo+Bev+Plat are reasonably recommended to balance PFS and OS, but adverse events should be considered. IT+aVEGFR+Plat shows potential superiority, but more clinical evidence is needed.

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Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Cited by 6 publications

References 22 publications

Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

PD-L2 glycosylation promotes immune evasion and predicts anti-EGFR efficacy

Therapeutic options for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer: a Bayesian network secondary analysis

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