Immunotherapy for EGFR-mutant advanced non-small-cell lung cancer: Current status, possible mechanisms and application prospects

Abstract

Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs.

Keywords: EGFR mutation; immune checkpoint inhibitors; non-small-cell lung cancer; programmed cell death 1; programmed cell death ligand 1; tumor microenvironment.

Figure 1

Clinical data of ICI-based immunotherapy for subtypes of EGFR-mutant NSCLC patients. (A) The PFS and OS of ICI-based immunotherapy for subtypes of EGFR-mutant NSCLC. (B) The ORR and DCR of ICI-based immunotherapy for subtypes of EGFR-mutant NSCLC. NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor; n, No. of EGFR mutant patients; ORR, overall response rate; DCR, disease control rate; OS, overall survival; PFS, progression-free survival; ICIs, immune checkpoint inhibitors; 19del, exon 19 deletion; Ex20 ins, exon 20 insertion.

Figure 2

The immunosuppressive TME throughout the whole cancer-immunity cycle in EGFR-mutant NSCLC. EGFR activation alters immune profiles through the following pathways: the surface of cancer cells creates a “do not eat me” signal that inhibits professional phagocytic cells, such as dendritic cells (DCs), from engulfing cancer cells due to the presentation of tumor antigens; promotes CTLA-4 expression to enhance the inhibitory function of Tregs; increases the infiltration of Tregs in the TME and promotes tumor growth; increases mast cells that contribute to angiogenesis and induces neovascularization by releasing proangiogenic factors; decreases CD8⁺ T-mediated antitumor activity, inhibiting the expression of MHC (Figure 2); enhances T-cell apoptosis, promoting the M2-like polarization of macrophages and increasing the levels of IL-10, CCL13, GDF15, CCL23, CXCL17, TGF-β, soluble PD-L1 and CCL2. CCL2 plays a critical role in the migration of MDSCs to the TME. MDSCs exert antitumor immunosuppressive actions, such as producing immunosuppressive molecules, inhibiting antitumor functions, inducing T-cell apoptosis, and upregulating Tregs. CAFs, with characteristics of MDSCs, in EGFR-mutant NSCLC might interfere with the immune response. EGFR-mutant tumors secrete exosomes containing EGFR mutations or PD-L1 to promote distant metastasis. EGFR-mutant tumor cells may change metabolic pathways, such as upregulating CD73 and converting ATP to adenosine. Massive adenosine exerts immunosuppressive activity on a variety of immune cells: Tregs and accumulation of MDSCs, further attenuating antitumor function in NKs, B cells and DCs activity, skews Mφ polarization toward M2 macrophages and inhibits the CTL-mediated antitumor response, mediating tumor immune evasion. NKs, natural killer cells; DCs, dendritic cells; IDC, immature dendritic cells; MDC, mature dendritic cells; Tregs, Treg cells; MHC, major histocompatibility complex; MDSC, myeloid-derived suppressor cells; EGFR, epidermal growth factor receptor; TME, tumor microenvironment; ATP, adenosine triphosphate; PD-L1, programmed death-ligand 1; Mφ, macrophages; CTL, cytotoxic T lymphocytes.

Figure 3

Multiple intrinsic cancer cell pathways induce cancer cell immune evasion in EGFR-mutant NSCLC. EGFR activating mutations may help cancer cells escape cytotoxic T-cell recognition and specific killing by promoting PD-L1 expression and downregulating MHC expression. The activation of EGFR may influence the expression of VEGF, inhibiting T lymphocyte infiltration into tumors, generating vascular endothelial growth and promoting tumor progression. In addition, activation of EGFR may influence the expression of CD47, decreasing the phagocytosis of cancer cells by DCs. In addition, EGFR-TKIs enhance MHC expression, and HypoTKI can induce more dsDNA and RNA release and trigger MyD88–type I IFN innate sensing pathways, which enhance tumor-specific T-cell infiltration and reactivation. EGFR, epidermal growth factor receptor; MEK/ERK, extracellular signal-regulated kinase (ERK) kinase MEK; MHC, major histocompatibility complex; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors; HypoTKI, low-fractionated EGFR-TKIs; DCs, dendritic cells.