Exploration of the Tumor-Suppressive Immune Microenvironment by Integrated Analysis in EGFR-Mutant Lung Adenocarcinoma

Abstract

BackgroundClinical evidence has shown that few non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can benefit from immunotherapy. The tumor immune microenvironment (TIME) is a significant factor affecting the efficacy of immunotherapy. However, the TIME transformational process in EGFR-mutation patients is unknown.MethodsThe mRNA expression and mutation data and lung adenocarcinoma (LUAD) clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Profiles describing the immune landscape of patients with EGFR mutations were characterized by differences in tumor mutation burden (TMB), ESTIMATE, CIBERSORT, and microenvironment cell populations-counter (MCP-counter).ResultsIn total, the TCGA data for 585 patients were analyzed. Among these patients, 98 had EGFR mutations. The TMB was lower in the EGFR group (3.94 mut/Mb) than in the KRAS mutation group (6.09 mut/Mb, P < 0.001) and the entire LUAD (6.58 mut/Mb, P < 0.001). The EGFR group had a lower population of activated immune cells and an even higher score of immunosuppressive cells. A further inter-group comparison showed that differences in the TMB and tumor-infiltrating lymphocytes were only found between patients with oncogenic mutations and unknown mutation. Meanwhile, there were more myeloid dendritic cells (DCs) in EGFR 19del than in L858R-mutation patients and in common mutation patents than in uncommon mutation patients (P < 0.05). Additionally, we established a D score, where D = MCP-counter score for cytotoxic T lymphocytes (CTLs)/MCP-counter score for myeloid DCs. Further analysis revealed that lower D scores indicated immune suppression and were negatively related to several immunotherapy biomarkers.ConclusionsThe TIME of EGFR mutant NSCLC was immunosuppressive. Myeloid DCs gradually increased in EGFR 19del, L858R, and uncommon mutations. The potential role of CTLs and DCs in the TIME of patients requires further investigation.

EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment

“…In this regard, it remains unclear whether there are differences in the TME and ICI efficacy in NSCLC with different EGFR mutation subtypes. Two recent studies have indicated that from an immunological perspective, oncogenic mutations may be an important factor for cellular immune-suppression [ 97 , 98 ]. Several potential approaches to improve the response to immunotherapy have been tested.…”

Characteristics of the immune microenvironment and their clinical significance in non-small cell lung cancer patients with ALK-rearranged mutation

“…In addition, a study showed that the TME of EGFR-mutant NSCLC was immunosuppressive ( 45 ). Previous studies reported that a high proportion of tumor-infiltrating lymphocytes (TILs), particularly those with cytotoxic functions, such as CD8+ and natural killer cells, are correlated with a favorable prognosis in various cancers ( 46 , 47 ).…”

Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer

“…As an oncogene, KRAS mutations were reported frequently in a variety of tumors, including colorectal cancer ( Prior et al, 2012 ), pancreatic cancer ( Arner et al, 2019 ), and bladder cancer ( Santha et al, 2020 ). Recent studies identified that KRAS might have a critical role in the immunoregulation of NSCLC ( Li et al, 2021 ; Wang et al, 2021 ). Our data also revealed that the 5mCscore had a markedly negative correlation with PD-L1 expression and the TMB.…”