EGFR‐targeted therapy alters the tumor microenvironment in EGFR‐driven lung tumors: Implications for combination therapies
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Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD‐1/PD‐L1) pathway have profoundly improved the clinical management of non‐small‐cell lung cancer (NSCLC). Nevertheless, the superiority of single‐agent PD‐1/PD‐L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR ‐driven lung tumor models to investigate dynamic microenvironmental responses to EGFR‐TKI treatment. We observed that at an early stage, sensitive EGFR‐TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8 + T cells and dendritic cells, eradication of Foxp3 + Tregs, and inhibition of M2‐like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune‐mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid‐derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR‐TKIs increased the levels of IL‐10 and CCL‐2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR‐TKIs in vivo . The results have implications for combination therapy using EGFR‐TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.
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EGFR-targeting agents such as gefitinib and osimertinib cause temporary accumulation of DCs and CD8+ TEFF cells with TREG and M2 TAM depletion in NSCLC, followed by MDSC-driven immunosuppression.
“temporary DC and CD8 + T EFF accumulation coupled to T REG cell and M2TAMdepletion, rapidly followed by MDSC-driven immunosuppression in vivo”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Jia et al., 2019
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- Authors
- Jia, Y., Li, X., Jiang, T., Zhao, S., Zhao, C., Zhang, L., Liu, X., Shi, J., Qiao, M., Luo, J., Liu, S., Han, R., Su, C., Ren, S., & Zhou, C.
- Affiliations
- Tongji University (CN)
- Corresponding author
- Zhou, Caicun
- ORCID
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2019-02-19
- Volume
- 145
- Issue
- 5
- Pages
- 1432-1444
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2913134141
- Cited by
- 164
- References
- 50
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 22 · 2023: 28 · 2022: 26 · 2021: 29 · 2020: 20 · 2019: 8
- FWCI
- 8.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81672286, 81871865, 81874036)
- Ministry of Science and Technology of the People's Republic of China (2016YFC0902302)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- anti-EGFR therapy, EGFR tyrosine kinase inhibitors, tumor microenvironment, non-small cell lung cancer, immune checkpoint inhibitors, PD-1/PD-L1 pathway, myeloid-derived suppressor cells, regulatory T cells, M2 macrophage polarization, CD8+ T cells, dendritic cells, IL-10, MCP-1, combination therapy
- MeSH terms
- Gefitinib, Adenocarcinoma of Lung, Acrylamides, Aniline Compounds, Animals, Antineoplastic Agents, Disease Models, Animal, Indoles, Lung Neoplasms, Macrophages, Mice, Transgenic, Pyrimidines, Random Allocation, Cytokines, Lymphocytes, Tumor-Infiltrating, Protein Kinase Inhibitors, Mice, Molecular Targeted Therapy, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor, ErbB Receptors
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