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.