Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

Abstract

Immunotherapy has been incorporated into the first- and second-line treatment strategies for non-small cell lung cancer (NSCLC), profoundly ushering in a new treatment landscape. However, both adaptive signaling and oncogenic (epidermal growth factor receptor (EGFR)-driven) signaling may induce PD-L1 upregulation in NSCLC. Nevertheless, the superiority of immune checkpoint inhibitors (ICIs) in advanced EGFR-mutant NSCLC is only moderate. ICIs appear to be well tolerated, but clinical activity for some advanced EGFR-mutant NSCLC patients has only been observed in a small proportion of trials. Hence, there are still several open questions about PD-L1 axis inhibitors in patients with NSCLC whose tumors harbor EGFR mutations, such as the effect of EGFR tyrosine kinase inhibitors (TKIs) or EGFR mutations in the tumor microenvironment (TME). Finding the answers to these questions requires ongoing trials and preclinical studies to identify the mechanisms explaining this possible increased susceptibility and to identify prognostic molecular and clinical markers that may predict benefits with PD-1 axis inhibition in this specific NSCLC subpopulation. The presence of multiple mechanisms, including dynamic immune TME profiles, changes in PD-L1 expression and low tumor mutational burdens, may explain the conflicting data regarding the correlation between PD-L1 axis inhibitors and EGFR mutation status. We conducted a review of this currently controversial topic in an attempt to aid in the decision-making process.

Keywords: Anti-PD-1/PD-L1 treatment; EGFR mutations; Immunotherapy; Non-small cell lung cancer; Tumor microenvironment.

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

Fig. 2

Intrinsic cancer cell pathways mediate the regulation of PD-L1 expression and MHC in EGFR-mutant NSCLC. Activation of EGFR may lead to downregulation of MHC expression through the MEK/ERK signaling pathway. In addition, activation of EGFR may influence expression of IFN-γR, generating intracellular signals that induce expression of the CIITA gene. CIITA is recruited to the MHC promoter, activating transcription. The net result is attenuation of CIITA and MHC molecule expression. In response to EGFR-TKIs, expression of CIITA and MHC genes is derepressed. In addition, EGFR-TKIs enhance MHC expression by inhibiting ERK activation. CIITA: class II major histocompatibility complex transactivator; TME: tumor microenvironment; MEK/ERK: extracellular signal–regulated kinase (ERK) kinase MEK; IFN-γR: interferon γ receptor; MHC: major histocompatibility complex; EGFR-TKIs: epidermal growth factor receptor tyrosine kinase inhibitors; EGFR: epidermal growth factor receptor; IFN-γ: interferon-γ

Fig. 3

Representative tumor characteristics and treatment regimens for NSCLC patients with EGFR mutations. TKI: tyrosine kinase inhibitors; EGFR: epidermal growth factor receptor; PD-L1: programmed death-ligand 1; ICIs: immune checkpoint inhibitors; T1: treatment 1; T2: treatment 2; Ate: atezolizumab; Bev: bevacizumab; Chemo: chemotherapy; (+): positive; (−): negative