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.