Brain Metastasis from EGFR‐Mutated Non‐Small Cell Lung Cancer: Secretion of IL11 from Astrocytes Up‐Regulates PDL1 and Promotes Immune Escape

Author:

Tang Mengyi1,Xu Mingxin1,Wang Jian1,Liu Ye2,Liang Kun1,Jin Yinuo1,Duan Wenzhe1,Xia Shengkai1,Li Guohui2,Chu Huiying2,Liu Wenwen13,Wang Qi1ORCID

Affiliation:

1. the Second Affiliated Hospital of Dalian Medical University 467 Zhongshan Road Dalian 116027 China

2. Laboratory of Molecular Modeling and Design State Key Laboratory of Molecular Reaction Dynamics Dalian Institute of Chemical Physics Chinese Academy of Science 457 Zhongshan Road Dalian 116023 China

3. Cancer Translational Medicine Research Center The Second Hospital, Dalian Medical University 467 Zhongshan Road Dalian 116027 China

Abstract

AbstractPatients 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.

Funder

National Natural Science Foundation of China

Liaoning Revitalization Talents Program

National Key Research and Development Program of China

Publisher

Wiley

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