Clinicopathologic Features and Immune Microenvironment of Non–Small-cell Lung Cancer With Primary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

We evaluated the clinical and immunopathologic features of non–small-cell lung cancer with primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors. The rate of smoking was significantly greater in those with primary resistance. The immune microenvironment characterized by low total tumor-infiltrating lymphocytes and negative programmed cell death ligand 1 correlated significantly with primary resistance. Background: Approximately 20% to 30% of non–small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKIs. Materials and Methods: The characteristics of 124 NSCLC patients with EGFR mutations who had received EGFR-TKIs were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFR-TKI treatment were assessed for the density of TILs expressing CD4 or CD8 and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically. Results: Primary resistance was observed in 13.7% of the patients (17 of 124). A significant difference in smoking history was observed between patients with primary resistance and those with non–primary resistance. A lower density of total TILs and negative PD-L1 expression on immunohistochemical analysis correlated significantly with primary resistance, in contrast to that with non–primary resistance. Moreover, the negative PD-L1 expression with low TIL density, indicating immune ignorant phenotype of tumor microenvironment, was observed in those with primary resistance with a significant difference. Conclusion: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs.