Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: from bed to bench

Abstract

Targeted therapies are efficient in the context of oncogenic driver mutations. Epidermal growth factor receptor (EGFR)-mutant lung cancers represent a distinct subset of non-small-cell lung cancer (NSCLC) with marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the high response rate to EGFR TKIs in EGFR-mutant lung cancer, resistance and tumor recurrence are unavoidable. Therapeutic options are restricted in patients after exhaustion of targeted therapies. Immune checkpoint inhibitors (ICIs) represent a novel therapeutic option for advanced NSCLC with significant overall survival benefit in registration trials. No superiority in terms of long-term survival was observed in the EGFR mutation subgroup when ICIs were given as monotherapy in second-line treatment in earlier studies. Thus, the appropriate application of ICIs to patients harboring EGFR mutations remains an important field of ongoing research. Here, we discuss different immune checkpoint blockade strategies, including ICIs alone and in combination with TKIs, chemotherapy, radiation, and antiangiogenic agents in EGFR-mutant NSCLC as first-line and subsequent treatments. We also summarize the evidence concerning the heterogeneous molecular features and immune signatures of EGFR mutations and their associations with ICI therapy outcomes. This study was performed to improve our understanding of the optimal mode of immune-based treatment approaches in EGFR-mutant NSCLC.

Keywords: epidermal growth factor receptor; immune checkpoint inhibitor; non-small-cell lung cancer; tumor microenvironment.

Figure 1.

Tumor microenvironment of EGFR-mutant NSCLC. EGFR protein expressed on the tumor cell surface could be activated by homodimerization, and may then activate downstream pathways. Mutant EGFR protein could bind to EGFR-TKI, thus blocking signal transduction. PD-L1 binding to PD-1 prevents T cells from recognizing tumor cells, thereby causing immune escape. PD-(L)1 inhibitor blocks PD-1 or PD-L1, promoting the binding of TCR on T cells to MHC molecules on tumor cells and reinitiating the immune response. Tumor antigens can be directly taken up by APC and presented to T cells. CD8⁺ TIL are major effector cells that produce an immune-mediated tumor-killing effect by secreting tumor toxic cytokines. EGFR mutation is associated with reduced density and function of CD8⁺ TIL, resulting in a poor response to ICIs. Treg is the predominant immunosuppressive cell type. AME released by mast cells could bind to EGFR expressed on Treg, promoting the function of Treg and indirectly promoting immunosuppression. CD73 expressed on tumor cells may induce the formation of adenosine, further promoting Treg and MDSC and hindering the immune response. Mutant EGFR is associated with upregulation of CD73. EGFR-containing exosomes are secreted by tumor cells and may drive metastasis. Tumor-induced neoangiogenesis leads to immunosuppression by promoting immunosuppressive cells and inhibiting effector T cells. Meanwhile, EGFR mutation is associated with reduced TMB, but its effect on PD-L1 expression is still controversial. Application of EGFR-TKI is suspected to cause dynamic changes in PD-L1 expression, but the specific effects remain unclear. The TME of EGFR-aberrant NSCLC represents a dynamic transition from beneficial in the early stages to immunosuppressive in later stages during EGFR-TKI treatment. Ag, antigen; AME, amphiregulin; APC, antigen presenting cell; CCL2, C–C motif chemokine ligand 2; DC, dendritic cell; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; IL-10, interleukin-10; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NSCLC, non-small-cell lung cancer; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TCR, T-cell receptor; TIL, tumor-infiltrating lymphocyte; TKI, tyrosine kinase inhibitor; TAM, tumor-associated macrophage; TMB, tumor mutation burden; TME, tumor microenvironment; Treg, regulatory T cell