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.

Establishment of Prediction Models for Lung Cancer NOG/PDX Models: A Guideline for Machine Learning in Small Biomedical Datasets

“…The largest coe cient of the number of the driver gene in the multivariable LR model also illustrates its absolute importance in developing non-patient-matched genotypes. Secondly, PDX models from EGFR mutant lung cancers were reported with poor histological differentiation, and frequent loss of EGFR mutations [34], which supported the high inconsistent risk of EGFR mutant NOG/PDX models in this study. Thirdly, the evidence that pemetrexed increased the number of TILs, and upregulated immune-related genes related to antigen presentation might support the conclusion that PDX models from patients receiving pemetrexed are less likely to maintain the original genotypes [35].…”

A Rare EGFR R748T Mutation in A Squamous Cell Lung Carcinoma Patient with PD-L1 High Expression and Response to Immuno-Chemo Combination Therapy

“…Furthermore, this study included 73% of patients with PD-L1 ≥ 50%, thus illustrating the poor response in EGFR-mutated NSCLC even with high PD-L1 expression [3]. Several reasons to these poor outcomes have been identi ed, such as the association of EGFR mutation with low tumor mutation burden (TMB) and the lack of T cell in ltration while PD-L1 expression is variable [2,13,14]. Nevertheless, some studies showed that patients with uncommon EGFR (including G719X, L861Q, S768I, and Ex20 ins) mutations have a good immunotherapy potential [15][16][17].…”

Identification of a gene signature closely related to immunosuppressive tumor microenvironment predicting prognosis of patients in EGFR mutant lung adenocarcinoma

“…The National Comprehensive Cancer Network (NCCN) guidelines do not recommend immunotherapy to patients with NSCLC harboring EGFR mutation at present [7][8]. Several mechanisms for poor responses to ICIs have been reported, such as a lower TMB and an unin amed and immunosuppressive TME [9][10][11][12][13][14][15][16]. PD-1/PD-L1 axis may not be the main immune escape route in EGFR mutant lung cancer.…”

“…Several studies have con rmed that EGFR mutations in NSCLC are closely related to an immunosuppressive tumor microenvironment (TME) [9][10][11][12][13] and a lower tumor mutation burden (TMB) [10,[14][15], which cause an inferior response to PD-1 blockade in NSCLCs. EGFR mutations can lead to an unin amed and immunosuppressive TME, with immunological tolerance, and weak immunogenicity [10,16].…”

“…Currently, a variety of bioinformatics tools are used to predict the distribution of immune cells by analyzing speci c gene signature [22][23][24]. In recent years, studies have shown that EGFR mutations may exert an anti-tumor immune response by affecting TME [9][10][11][12][13]. EGFR mutant LUAD patients have a unique TME, which may be different from wild-type EGFR patients.…”