Introduction
Lung cancer is the most common cancer and a leading cause of death from
cancer in men and women in the world with a 5-year survival rate about
19%[1]. According to the global cancer statistics, the incidence
and mortality of lung cancer in the male population ranked first place
in the world’s malignant tumor, and incidence in the female population
ranked third place, mortality ranked second place[2]. In China, the
incidence and mortality of lung cancer are the highest in the male
population, and the incidence in the female is second place, and
mortality is the first place[3].
Epidermal growth factor receptor (EGFR), also known as ERBB1 and HER1,
is a transmembrane tyrosine kinase receptor (RTK), which is a member of
the human epidermal receptor (HER) family and a crucial component of
cell signal pathways[4]. Overexpression and mutation of EGFR can
lead to activation of important signaling pathways, such as Ras-MAPK,
PI3K-Akt, and STAT, increasing cell proliferation, angiogenesis, and
metastasis[5]. About 40% to 80% of patients with non-small cell
lung cancer (NSCLC) have EGFR mutation or overexpression[6]. Among
them, EGFR mutations were found in 15% of Caucasians and 30-50% of
Asian NSCLC patients[7-9]. Epidermal growth factor receptor tyrosine
kinase inhibitors (EGFR-TKIs), which are classic small molecule
inhibitors can inhibit the EGFR tyrosine kinase domain reversibly
through competitive binding with ATP[10]. At present, EGFR-TKIs
commonly used in the clinic include gefitinib and erlotinib of the first
generation, afatinib and dacomitinib of the second generation, and
osimertinib of the third generation. Several clinical trials have shown
that EGFR-TKIs can prolong the survival time of patients with tumors
harboring EGFR-activating mutations[11-33]. The main clinical trials
are shown in Table.
However, patients initially responding to EGFR-TKIs invariably develop
resistance and the median progression free survival was about 10
months[11, 16, 23, 30]. Resistance to EGFR-TKIs is inevitable due to
various mechanisms, such as the secondary mutation known as
T790M(50%)[34]; MET amplification(5%), HER-2 amplification(8%),
PI3K mutation(5%), histologic transformation(14%)[35, 36]; new
mutations like EFGR-C797S mutation, EGFR-L792H mutation and
EGFR-G796R[37-39]. Previous studies focused too much on drug
resistance caused by tumor cells, and few on tumor immune
microenvironment. Therefore, it is imperative to study the mechanism of
tumor immune microenvironment in tumor drug resistance. The tumor immune
microenvironment (TIME) contains numerous cell types in addition to
cancer cells, which include bone marrow-derived inflammatory cells,
lymphocytes, blood vessels, fibroblastic cells, and the extracellular
matrix composed of collagen and proteoglycans[40, 41]. Next, this
review will describe the TIME of NSCLC with EGFR mutation in five
aspects: tumor extracellular matrix; Cancer-associated fibroblasts;
Tumor vasculature; tumor infiltrating immune cells; Cytokines secreted
by tumor and immune cells.