EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer
Open accessAbstract
Patients with EGFR mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between EGFR mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression, and the association of EGFR status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10–2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression. Furthermore, patients with EGFR mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1+/CD8+ TIL (P = 0.034). Importantly, patients with EGFR mutations, especially the sensitive subtype, showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with EGFR wild-type did (HR = 0.73, P < 0.00001). This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs.
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NSCLCs harboring EGFR mutations show lower benefit with anti-PD-1/PD-L1 agents compared with EGFR wild type.
“Mounting evidence suggests that NSCLCs harboring EGFR mutations show lower benefit with the use of anti-PD-1/PD-L1 agents, compared with EGFR wild type.”
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- Authors
- Dong, Z.-Y., Zhang, J.-T., Liu, S.-Y., Su, J., Zhang, C., Xie, Z., Zhou, Q., Tu, H.-Y., Xu, C.-R., Yan, L.-X., Li, Y.-F., Zhong, W.-Z., & Wu, Y.-L.
- Affiliations
- Guangdong General Hospital (CN)
- Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- Corresponding author
- Zhong, Wen-Zhao
- Wu, Yi-Long
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2017-07-26
- Volume
- 6
- Issue
- 11
- Pages
- e1356145
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5674946
- OpenAlex
- W2737044461
- Cited by
- 440
- References
- 38
- Citations by year
- 2026: 21 · 2025: 48 · 2024: 60 · 2023: 57 · 2022: 66 · 2021: 73 · 2020: 51 · 2019: 34 · 2018: 29 · 2017: 1
- FWCI
- 13.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- OncoImmunology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Health and Family Planning Commission of the People's Republic of China (201402031)
- National Key Research and Development Program of China (2016YFC 1303800, 201402031)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- EGFR mutation, non-small cell lung cancer, anti-PD-1 therapy, PD-L1 expression, tumor immune microenvironment, tumor-infiltrating lymphocytes, CD8+ T cells, tumor mutational burden, immunotherapy resistance, early-stage lung cancer, immunogenicity
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