ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
IL6 Mediates Suppression of T- and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 126 citations in OpenAlex.
- IL-6/IL-6R-Mediated Mechanisms in Lung Cancer: From Pathogenesis to Potential Therapeutic Targets.Immunology · 2026Review
- Molecular insights and therapeutic implications for the tumor suppressor role of LKB1 in non-small cell lung cancer.Cancer letters · 2026Review
- Tumor cell-intrinsic NSUN2 deficiency reprograms macrophages to sensitize non-small cell lung cancer to EGFR inhibitors by reversing immune evasion.Neoplasia (New York, N.Y.) · 2026Article
- Modeling blood-brain barrier-glioblastoma interactions: implications for chemoresistance and therapeutic targeting.Fluids and barriers of the CNS · 2026Review
- A clinical decision framework for redox-adapted, EMT-high cancers: From ferroptosis resistance to precision therapeutic stratification.Redox biology · 2026Review
- DNA base lesion-containing G-quadruplex mediates transcriptome reprogramming in EGFR-TKI resistance of non-small cell lung cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- IL‑6: A key player in the EGFR‑TKI‑resistant tumor microenvironment and its therapeutic implications (Review).International journal of oncology · 2026Review
- <p>Immunotherapy after EGFR‑TKI treatment in advanced non‑small cell lung cancer: Current status and future perspectives (Review)</p>.Oncology reports · 2026Review
- Osimertinib activates a TGF-β2-dependent secretory program that drives lung adenocarcinoma progression.The Journal of clinical investigation · 2026Article
- Protective NK Cell Reservoir Based on DNA Supramolecular Hydrogel for Enhanced Triple-Negative Breast Cancer Therapy.Research (Washington, D.C.) · 2026Article
- Taxanes Versus Pemetrexed After Osimertinib Resistance in EGFR-Mutated NSCLC: A Retrospective Cohort with Two-Model In Vitro Validation.Cancer management and research · 2026Article
- Efficacy and mechanisms of immune checkpoint inhibitors in late-stage EGFR-mutated non-small cell lung cancer following targeted therapy resistance.Frontiers in immunology · 2026Review
- Astragaloside IV Co-Loaded Osimertinib Liposomes Alleviate EGFR-TKI Resistance in Non-Small Cell Lung Cancer.International journal of nanomedicine · 2026Article
- A novel mouse cell line model reveals the tumor intrinsic and immune characteristics of EGFR-mutant lung cancer.Theranostics · 2026Article
- CAR-NK Engineering to Overcome TME Barriers.Cells · 2025Review
- Prognostic and immunological potential of AC012236.1/hsa-miR-30d-5p CeRNA of AVEN by integrated analysis of single-cell and bulk RNA-seq in lung adenocarcinoma.Scientific reports · 2025Article
- GLMP promotes EGFR-TKI resistance by activating autophagy and RhoA pathway in non-small cell lung cancer.NPJ precision oncology · 2025Article
- Neutrophils in non-small cell lung cancer and immunotherapy with PD-1/PD-L1 inhibitors.Journal of translational medicine · 2025Review
- Mechanistic insights into IL-6-mediated NK cell dysfunction in NSCLC via the IRE1α-XBP1s-STAT3-UBE2S axis.NPJ precision oncology · 2025Article
- The Activity of EGFR CAR NK and CAR T Cells against EGFR Inhibitor-Resistant NSCLC and Drug-Tolerant Persister Cells.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 1 institution in 1 country.
Funding
Abstract
purposePatients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype. EXPERIMENTAL
designWe utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and the combined efficacy of IL6 inhibition and anti-PD-1 therapy. Corresponding in vitro studies used EGFR-mutant human cell lines and clinical specimens.
resultsWe identified that EGFR-mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL6 secretion. In EGFR-mutant GEMMs, IL6 depletion enhanced activation of infiltrating natural killer (NK)- and T-cell subpopulations and decreased immunosuppressive regulatory T and Th17 cell populations. Inhibition of IL6 increased NK- and T cell-mediated killing of human osimertinib-resistant EGFR-mutant NSCLC tumor cells in cell culture. IL6 blockade sensitized EGFR-mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ+ CD8+ T cells.
conclusionsThese data indicate that IL6 is upregulated in EGFR-mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T- and NK-cell function. IL6 blockade enhanced antitumor immunity and efficacy of anti-PD-1 therapy warranting future clinical combinatorial investigations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.