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Updated: Jan 28, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: Implications for combination
Yijun Jia1, Xuefei Li2, Tao Jiang1
1Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China.
Abstract:
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.
Insights
EGFR-TKI treatment in lung cancer initially improves anti-tumor immunity but this effect is temporary. Myeloid-derived suppressor cells increase, suggesting combination therapies need careful timing and immune modulation strategies.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 pathway improve non-small-cell lung cancer (NSCLC) management.
- Single-agent PD-1/PD-L1 inhibitors show moderate efficacy in pretreated EGFR-mutant NSCLC patients.
- An immunosuppressive tumor microenvironment is a proposed mechanism for poor ICI response.
Purpose of the Study:
- To investigate dynamic tumor microenvironmental responses to EGFR-TKI treatment in EGFR-driven lung cancer models.
- To understand how EGFR-TKI therapy impacts immune cells and inflammatory factors in the tumor microenvironment.
- To inform combination strategies involving EGFR-TKIs and immunotherapies.
Main Methods:
- Utilized two autochthonous EGFR-driven lung tumor models in vivo.
- Analyzed dynamic changes in tumor-infiltrating immune cells (CD8+ T cells, Tregs, macrophages, MDSCs) during EGFR-TKI treatment.
- Measured serum inflammatory factors including IL-10 and CCL-2.
Main Results:
- Early-stage EGFR-TKI treatment led to tumor shrinkage, increased CD8+ T cells and dendritic cells, Treg eradication, and reduced M2 macrophage polarization.
- Beneficial immune changes were transient, diminishing with continued EGFR-TKI treatment.
- Myeloid-derived suppressor cells (MDSCs), especially mononuclear MDSCs, were consistently elevated.
- EGFR-TKIs increased serum levels of IL-10 and CCL-2.
Conclusions:
- EGFR-TKI treatment induces dynamic, temporary changes in the lung tumor microenvironment.
- Sustained elevation of MDSCs and increased IL-10/CCL-2 suggest an evolving immunosuppressive state.
- Optimizing combination therapy requires careful consideration of treatment sequencing and strategies to modulate the tumor microenvironment for enhanced antitumor immunity.
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