Brain Metastasis from EGFR-Mutated Non-Small Cell Lung Cancer: Secretion of IL11 from Astrocytes Up-Regulates PDL1 and Promotes Immune Escape.
Mengyi TangMingxin XuJian WangYe LiuKun LiangYinuo JinWenzhe DuanShengkai XiaGuohui LiHuiying ChuWenwen LiuQi WangPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
Patients who have non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are more prone to brain metastasis (BM) and poor prognosis. Previous studies showed that the tumor microenvironment of BM in these patients is immunosuppressed, as indicated by reduced T-cell abundance and activity, although the mechanism of this immunosuppression requires further study. This study shows that reactive astrocytes play a critical role in promoting the immune escape of BM from EGFR-mutated NSCLC by increasing the apoptosis of CD8 + T lymphocytes. The increased secretion of interleukin 11(IL11) by astrocytes promotes the expression of PDL1 in BM, and this is responsible for the increased apoptosis of T lymphocytes. IL11 functions as a ligand of EGFR, and this binding activates EGFR and downstream signaling to increase the expression of PDL1, culminating in the immune escape of tumor cells. IL11 also promotes immune escape by binding to its intrinsic receptor (IL11Rα/glycoprotein 130 [gp130]). Additional in vivo studies show that the targeted inhibition of gp130 and EGFR suppresses the growth of BM and prolongs the survival time of mice. These results suggest a novel therapeutic strategy for treatment of NSCLC patients with EGFR mutations.
Keyphrases
- epidermal growth factor receptor
- small cell lung cancer
- advanced non small cell lung cancer
- poor prognosis
- tyrosine kinase
- end stage renal disease
- ejection fraction
- newly diagnosed
- long non coding rna
- brain metastases
- peritoneal dialysis
- prognostic factors
- white matter
- cell cycle arrest
- type diabetes
- cell proliferation
- multiple sclerosis
- patient reported outcomes
- skeletal muscle
- cancer therapy
- high fat diet induced
- dna binding
- insulin resistance