Cytokines secreted by tumor and immune cells
Cytokines are small molecular proteins with extensive biological activities synthesized and secreted by immune cells and non-immune cells through stimulation, including interleukin, interferon, tumor necrosis factor superfamily, colony stimulating factor, chemokines, growth factors, etc.[107], which play an important role in tumor inhibition, proliferation and metastasis (Figure 3). Studies have found that in EGFR mutant lung cancer, alveolar macrophages downregulated surface expression of MHC-II and costimulatory molecules; increased production of CXCL1, CXCL2, IL1 receptor antagonist; and increased phagocytosis. EGFR-TKIs can decrease alveolar macrophages in EGFR mutant lung cancer[108]. It has been found that EGFR-TKIs can induce PD-L1 protein degradation in NSCLC cells with EGFR mutation through the GSK3 β pathway and ubiquitin protease pathway, which contributed to T cell activation[109]. In addition, EGFR mutation can up regulate amphiregulin (AREG) and AREG maintained the Treg cell suppressive function via the EGFR/GSK-3β/Foxp3 axis, furthermore, inhibition of EGFR by EGFR-TKIs restored the activity of GSK-3β and attenuated Treg cell function[110].
As for EGFR-TKIS resistance, it was found that Axl kinase was overexpression in EGFR-TKI resistant NSCLC, which was positively correlated with the expression of genes encoding immune checkpoint molecules (CD274, CTLA4), chemokine receptors (CXCR4, CXCR6), or chemokines (CXCL16). These chemokines can induce tumor invasion and metastasis. Inhibition of Axl kinase activity can reduce the expression of these chemokines[111]. In addition, studies have found that overexpression of hepatocyte growth factor (HGF) induces EMT through the HGF-MET pathway, resulting in EGFR-TKIs resistance[112-120]. MiR-1-3p and miR-206 can reverse HGF-induced EGFR-TKIs resistant lung cancer through inhibition of c-Met signaling and EMT[121]. Overexpression of PD-L1 is one of the mechanisms of EGFR-TKIs primary resistance. Studies have found that PD-L1 led to EGFR-TKIs primary resistance by inducing EMT through the TGF-β/Smad3 pathway. Inhibition of the TGF-β/Smad3 pathway can reverse EGFR-TKIs resistance[122-124]. Moreover, the activation of the TGF-β/Smad2 pathway can induce EMT and EGFR-TKIs resistance by increasing the expression of CXCR4[124, 125]. The study also found that TGF-β can induce EMT and EGFR-TKIs resistance by increasing the expression of PCKα[126]. In addition, TGF-β1 can induce EGFR-TKIs resistance by activating the Akt-ERK pathway, increasing the expression of MIG6, and decreasing the expression of PTEN[127, 128].
It was found that overexpression of IL-6 in EGFR-mutant NSCLC was correlated with EGFR-TKIs resistance[129]. In addition, the activation of the adrenergic β2 receptor can induce EGFR-TKIs resistance by increasing the expression of IL-6[130]. For the detection of serum cytokines in NSCLC with EGFR mutation, the study found that patients with high levels of IL-6, VEGF, and HGF in serum had a poor response to EGFR-TKIs treatment. Dynamic change of these cytokines in blood during TKIs treatment can predict the efficacy of EGFR-TKIs[131, 132]. Studies have found that RNF25 promoted EGFR-TKIs resistance in EGFR-mutant NSCLC cells by inducing ERK reactivation through the expression of IL6 via the NK-κB signal pathway, and inhibition of RNF25 or NF-κB and ERK pathways can reverse EGFR-TKIs resistance[133]. In addition, studies have found that overexpression of miR-762 which was induced by IL6, promoted EGFR-TKIs resistance in NSCLC through posttranscriptional repression of active BCR related protein (ABR)[134]. Not only IL-6 can induce EGFR-TKIs resistance, but also IL-8 can induce EGFR-TKIs resistance by EMT through activation the MAPK singnal pathway[135].
Integrin linked kinase (ILK) regulates the interaction between tumor cells and the extracellular environment, activates signal pathway, promotes cell proliferation, migration and EMT. SHP2 is crucial for the activation of the receptor tyrosine kinase signal pathway. Studies have found that ILK and SHP are highly expressed in EGFR-TKIs resistant NSCLC[136]. Other studies have found that secreted phosphoprotein 1 (SPP1) was significantly increased in EGFR-TKIs resistant lung cancer cells, and inhibition of SPP1 increased sensitivity of lung cancer cells to EGFR-TKIs and decrease the ability of invasion[137]. Overexpression of type 1 insulin-like growth factor receptor (IGF1R) is associated with EGFR-TKIs resistance. Studies have found that overexpression of IGF1R can promote EGFR-TKIs resistance by inducing EMT of tumor cells, and inhibition of IGF1R can reverse EMT of tumor cells and sensitivity to EGFR-TKIs[138]. CXCR7, an atypical G protein-coupled receptor, can promote EGFR-TKIs resistance by EMT of tumor cells through activation of MAPK-ERK pathway via β-arrestin[139]. There are many studies on the relationship between cytokines and EGFR mutation and EGFR-TKIs resistance, involving complex and diverse signaling pathways, which can be classified as one point, namely tumor EMT. Therefore, inhibitors targeting multiple pathways of EMT may be one of the research directions for reversing EGFR-TKIs resistance.