Abnormal activation of NF-κB and MAPK signaling pathways affect osimertinib resistance and influence the recruitment of myeloid-derived suppressor cells to shape the immunosuppressive tumor immune microenvironment

Chao Wang; Kailun Fei; Lihui Liu; Jianchun Duan; Zhijie Wang; Sini Li; Jiachen Xu; Xue Zhang; Yanhua Tian; Yan Qu; Hua Bai; Jie Wang

doi:10.1111/1759-7714.14929

Abnormal activation of NF-κB and MAPK signaling pathways affect osimertinib resistance and influence the recruitment of myeloid-derived suppressor cells to shape the immunosuppressive tumor immune microenvironment

Thorac Cancer. 2023 Jul;14(19):1843-1856. doi: 10.1111/1759-7714.14929. Epub 2023 May 23.

Authors

Chao Wang^{1

2}, Kailun Fei^{1

2}, Lihui Liu^{1

2}, Jianchun Duan^{1

2}, Zhijie Wang^{1

2}, Sini Li¹, Jiachen Xu^{1

2

3}, Xue Zhang¹, Yanhua Tian¹, Yan Qu¹, Hua Bai^{1

2}, Jie Wang^{1

2}

Affiliations

¹ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Guangdong Provincial People's Hospital/Guangdong Provincial Academy of Medical Sciences, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong, China.

Abstract

Background: Osimertinib is the first-line treatment for patients with epidermal growth factor receptor (EGFR) mutations, but the treatment options after drug resistance are limited. Previous studies have suggested that EGFR is in an immunosuppressive tumor immune microenvironment (TIME). However, the evolution of TIME after osimertinib resistance and whether this resistance can be overcome by targeting TIME needs to be further investigated.

Methods: The remodeling process and mechanism of TIME during the treatment with osimertinib were studied.

Results: The proportion of EGFR^L858R+T790M mutant tumor immune infiltrating cells was extremely low. Osimertinib treatment transiently triggered inflammatory cells, but several immunosuppressive cells infiltrated after drug resistance and formed a myeloid-derived suppressor cell (MDSC)-enriched TIME. The programmed cell death protein-1 monoclonal antibody was not able to reverse the MDSC-enriched TIME. Further analysis revealed that the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways recruited a large number of MDSCs via cytokines. Finally, MDSC secreted high levels of interleukin-10 and arginase-1 and created an immunosuppressive TIME.

Conclusions: Thus, our findings lay the foundation for the evolution of TIME in osimertinib treatment, establish the mechanism of immunosuppressive TIME after osimertinib resistance, and propose potential solutions.

Keywords: EGFR; MDSC; TIME; lung cancer; osimertinib resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / pathology
Drug Resistance, Neoplasm / genetics
ErbB Receptors / genetics
Humans
Lung Neoplasms* / pathology
Mutation
Myeloid-Derived Suppressor Cells* / metabolism
Myeloid-Derived Suppressor Cells* / pathology
NF-kappa B / genetics
Protein Kinase Inhibitors / therapeutic use
Signal Transduction
Tumor Microenvironment

Substances

osimertinib
ErbB Receptors
NF-kappa B
Protein Kinase Inhibitors