Fig. 1.

A major hallmark of immunosuppression in the TME through diverse pathways in EGFR-mutant NSCLC. EGFR-mutant tumor cells may upregulate CD73, convert ATP to ADO, which binds with subtypes of ADO receptors, and upregulate expression of Tregs by bypassing ADO, mediating tumor cell metastasis and proliferation. Abundant ADO exerts immunosuppressive activity on a variety of immune cells. It promotes activation of Tregs and accumulation of MDSCs, further attenuating antitumor function in NK and DC activity, skews Mφ polarization toward M2 macrophages and inhibits the Teff-mediated antitumor response, mediating tumor immunity escape. EGFR-TKIs alter immune profiles through the following pathways: enhancing expression of MHC (Fig. 2); promoting Foxp3 degradation to attenuate the inhibitory function of Tregs; reducing infiltration of Tregs in the TME and inhibiting tumor growth; and enhancing Teff-mediated antitumor activity, reducing T cell apoptosis, inhibiting M2-like polarization of macrophages and increasing levels of IL-10 and CCL2. CCL2 binds to its receptor CCR2 to act as a chemokine ligand, playing a critical role in the migration of MDSCs to the TME. In addition, CCL2 can upregulate and activate the STAT3 pathway of MDSCs. STAT3 further mediates the amplification and activation of MDSCs. MDSCs exert antitumor immunosuppressive actions, such as producing immunosuppressive molecules, inhibiting antitumor functions, inducing T cell apoptosis, and upregulating Tregs. However, EGFR-TKIs have a dynamic effect on the tumor immune microenvironment and modify the TME in several ways. AREG might regulate the efficiency of Treg-mediated immune modulation via the EGFR/GSK-3β/Foxp3 axis. GSK-3β-phosphorylated Foxp3 induces subsequent ubiquitination and degradation of Foxp3. Furthermore, loss of Foxp3 protein expression may be linked to impaired function of Tregs by affecting Foxp3 protein stability and its ability to bind to gene promoters. Exosomal PD-L1 suppresses T cell activity in draining lymph nodes (in mouse models). STAT3: signal transducer and transcriptional activator-3; CCL2: C-C motif chemokine ligand 2; Foxp3: forkhead box P3; NKs: natural killer cells; DCs: dendritic cells; Tregs: Treg cells; ADO: adenosine; Teffs: effector T cells; MHC: major histocompatibility complex; EGFR-TKIs: epidermal growth factor receptor tyrosine kinase inhibitors; MDSCs: myeloid-derived suppressor cells; IL-10: interleukin 10; GSK-3β: glycogen synthase kinase 3β; EGFR: epidermal growth factor receptor; TME: tumor microenvironment; CCR2: C-C motif chemokine receptor 2; ATP: adenosine triphosphate; PD-L1: programmed death-ligand 1; Tc: tumor cells; Mφ: macrophages; CD8+ T cells: cytotoxic T cells; TH1 cells: type 1 T helper cells