EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells

Yu, Shengwen; Sha, Huanhuan; Qin, Xingzhen; Chen, Yan; Li, Xiaoyou; Shi, Meiqi; Feng, Jifeng

doi:10.1038/s41388-020-1182-y

Cited by 49 publications

(39 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…144 In-vitro studies also indicate a direct immunosuppressive effect of dendritic cells mediated by exosomes of EGFR Del19 cells. 145 Together these results suggest that further stratification of EGFR M+ NSCLC might allow a better patient stratification and selection for immune checkpoint inhibitor treatment.…”

Section: Discussionmentioning

confidence: 82%

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Meisel

Prof

2020

healthbook TIMES Onco Hema

View full text Add to dashboard Cite

Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A) 1 , which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B). 2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed 1,3,4 , but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype. 5-7 The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). 5 Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signalling cascades. 5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/ RAF/MEK and PI3K/AKT pathways, among others. 5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients. 5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signalling. 8 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C). 9 Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, anti-tumor activity (Table 1A) and safety. 10 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance. 11 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation. 12 Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progressionfree survival (PFS) relative to those treated with first-generation EGFR-TKIs. 13, 14 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the EGFR T790M mutation who had disease progression with first-and second-generation EGFR-TKIs. 15 Although the treatment landscape of advanced NSCLC has dramatically ch...

show abstract

Section: Discussionmentioning

confidence: 82%

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Meisel

Prof

2020

healthbook TIMES Onco Hema

View full text Add to dashboard Cite

show abstract

“…However, long-term follow-up of these clinical trials and some case reports showed that a group of EGFR mutated NSCLC patients sustained a durable response. Most studies focused on elucidating the underlying mechanism of the negative clinical outcomes ( 22 – 25 ). Little efforts have been made to stratify a small group of patients with EGFR driver mutation, who are likely to benefit from immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…With the development of next-generation sequencing (NGS) technologies and bioinformatics algorithms, neoantigen can be successfully identified in silico in many solid tumors (20). Monitoring neoantigen-specific T-cell response to anti-PD-1/PD-L1 blockades in peripheral blood has become a feasible way to predict the prognosis of cancer patients (13,21). Nevertheless, only a small amount of neoantigens were identified to be truly immunogenic, and clinical applications based on neoantigens are still in its infancy stage (17).…”

Section: Introductionmentioning

confidence: 99%

Identification of Clonal Neoantigens Derived From Driver Mutations in an EGFR-Mutated Lung Cancer Patient Benefitting From Anti-PD-1

Liu

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been recommended as the first-line therapy for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, acquired resistance to EGFR-TKIs is inevitable. Although immune checkpoint blockades (ICBs) targeting the programmed cell death 1 (PD-1)/PD-ligand (L)1 axis have achieved clinical success for many cancer types, the clinical efficacy of anti-PD-1/PD-L1 blockades in EGFR mutated NSCLC patients has been demonstrated to be lower than those without EGFR mutations. Here, we reported an advanced NSCLC patient with EGFR driver mutations benefitting from anti-PD-1 blockade therapy after acquiring resistance to EGFR-TKI. We characterized the mutational landscape of the patient with next-generation sequencing (NGS) and successfully identified specific T-cell responses to clonal neoantigens encoded by EGFR exon 19 deletion, TP53 A116T and DENND6B R398Q mutations. Our findings support the potential application of immune checkpoint blockades in NSCLC patients with acquired resistance to EGFR-TKIs in the context of specific clonal neoantigens with high immunogenicity. Personalized immunomodulatory therapy targeting these neoantigens should be explored for better clinical outcomes in EGFR mutated NSCLC patients.

show abstract

“…Similar to PD-L1, its expression can be induced by immune cell-secreted inflammatory cytokines, such as, IFNs, IL-4, IL-10, and granulocyte/macrophage colony-stimulating factor, but also by intracellular oncogenic signaling that can contribute to intrinsic immune resistance. PD-L2 expression significantly correlated with PD-L1 expression in different NSCLC gene expression datasets, and both PD-L1 and PD-L2 expression were associated with specific gene signatures, suggesting a potential role for PD-L2 and these gene expression biomarkers in predicting clinical responses to immune checkpoint blockade [ 201 ].…”

Section: Perspectives: Potential Role For Pdcd1 and Pdcd1lg1 Genementioning

confidence: 99%

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

Santarpía

Aguilar

Chaib

et al. 2020

Cancers

View full text Add to dashboard Cite

Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.

show abstract

EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells

Cited by 49 publications

References 32 publications

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Identification of Clonal Neoantigens Derived From Driver Mutations in an EGFR-Mutated Lung Cancer Patient Benefitting From Anti-PD-1

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

Contact Info

Product

Resources

About