EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment

Abstract

Lung cancer is a leading cause of cancer-related deaths worldwide. About 10–30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-γ, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development.

Analyses of single extracellular vesicles from non-small lung cancer cells to reveal effects by Epidermal growth factor inhibitor treatments

“…EGFR -mutant NSCLC cases are reported to “immune cold” relative to other cases because of multiple alterations in the tumor cells per se e.g., increased PD-L1 expression but also because of changes in the tumor microenvironment [19]. PD-L1 is also reported in EVs from NSCLC cells including those with EGFR-mutations and as a next step in our analyses we therefore studied heterogeneity in PD-L1 expression in EVs isolated from cell culture media of H1975 cells prior and post EGFR-TKI treatment [18].…”

“…By combining the results from the numerical data with the intensities it seems like the EVs isolated post EGFR-TKI treatment are more positive to PD-L1, but with reduced number of proteins per vesicle. As it has been demonstrated in other tumor types that PD-L1 expressing EVs may block effect of ICI treatment it is interesting to note that PD-L1 alterations occur on EVs after EGFR-TKI which may indeed contribute to the observed immune cold phenotype of EGFR-mutant NSCLC cases [29], [19], [38], [39], [40].…”

“…Multiple studies in different tumor types have also demonstrated that EGFR signaling may influence the EVs released in terms of tetraspanin CD9, CD63, CD81 expression as well as other proteins [16] [17]. Moreover, it has been demonstrated that EVs contain various immune signaling components including PD-L1 which could contribute to an immune suppressive phenotype seen among NSCLC cases and which influence immune checkpoint inhibitor treatments [18] [19]. Yet, most of these EV studies have focused on bulk analyses of EVs, thereby missing the hidden signatures in the heterogenous EV population as well as the aspect of tumor heterogeneity which can have major impact on the diagnostic accuracy and scope.…”

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

“…On the other hand, some studies also reported that the responsiveness or tolerance to immunotherapy was significantly related with tumor mutations ( 43 , 44 ). Thus, we analyzed the mutation profiles and found that the TMB between C1 and C2 was similar.…”

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

“…Although we did not compare the TMB levels according to EGFR mutational status, our study confirmed previous findings of relatively low TMB levels in EGFR -positive tumors. Evidence indicates that ICIs are not effective in the oncogene-driven lung cancers, and it is partly due to an immunosuppressive tumor microenvironment (TME) in such tumors, including the recruitment of tumor-associated macrophages and regulatory T-cells and the production of inhibitory cytokines that are induced by the activated EGFR signaling [ 23 ]. TMB represents the mutational load in the tumor cell genome and serves as a surrogate marker for tumor neoantigen production and potential immunogenicity.…”