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Differences in Immunological Landscape between EGFR-Mutated and Wild-Type Lung Adenocarcinoma
Jia-Wei Luo1, Yan-Hua Guo2, Feng-Ying Wu1
1Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China.
Abstract:
Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients (P = 0.0065). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.
Insights
Lung adenocarcinoma patients with EGFR mutations show poor immunotherapy response due to distinct tumor microenvironments. Wild-type EGFR tumors have better disease-free survival, suggesting different treatment strategies are needed.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy in lung adenocarcinoma patients with Epidermal Growth Factor Receptor (EGFR) mutations.
- The underlying mechanisms for this poor response remain unclear.
- Understanding the tumor microenvironment (TME) is crucial for optimizing cancer immunotherapy.
Purpose of the Study:
- To investigate and compare the TME characteristics between lung adenocarcinoma patients with and without EGFR mutations.
- To identify potential mechanisms explaining the differential response to ICIs based on EGFR mutation status.
Main Methods:
- Retrospective analysis of 323 lung adenocarcinoma patients (164 with EGFR mutations).
- Immunohistochemistry analysis of resected tumor tissues.
- Assessment of immune checkpoint molecules (PD1, PD-L1, LAG-3) and immune cells (CD3, CD4, CD8, Foxp3) within the TME.
Main Results:
- Significant differences in TME composition were observed between EGFR-mutant and wild-type tumors.
- EGFR-mutant tumors exhibited higher expression of CD3, CD4, PD-L1, and Foxp3 compared to wild-type tumors.
- EGFR-wild-type tumors showed a positive correlation with LAG3 and PD-1 expression.
- EGFR-wild-type patients had significantly longer disease-free survival (DFS) than EGFR-mutant patients (P=0.0065).
Conclusions:
- EGFR mutation status significantly influences the TME composition in lung adenocarcinoma.
- Distinct TME profiles in EGFR-mutant versus wild-type tumors may underlie the differential response to ICIs.
- These findings offer insights into the mechanisms of ICI resistance and inform future therapeutic strategies.
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