关键词: 非小细胞肺癌, EGFR T790M突变, EGFR TKI, 免疫微环境

Abstract:

Background and purpose: Epidermal growth factor receptor exon 20 T790M (EGFR T790M) mutation is one of the acquired resistance mechanisms in non-small cell lung cancer (NSCLC) against first-/second-generation EGFR tyrosine kinase inhibitors (EGFR TKIs). Additionally, EGFR T790M mutation can also be observed in NSCLC patients who have not undergone EGFR TKIs treatment. This study aimed to compare the clinical pathological characteristics and prognostic differences between NSCLC patients with de novo and acquired EGFR T790M mutation, and further explore the immune microenvironment features of acquired T790M mutation in NSCLC. Methods: This study retrospectively included 3 762 cases of NSCLC diagnosed at Fudan University Shanghai Cancer Center from April 2020 to September 2022. Among them, 2 070 cases (55.02%) exhibited EGFR mutations, and 556 cases (14.77%) received EGFR TKIs treatment. Specifically, there were 119 cases (3.16%) of NSCLC with EGFR T790M mutation, including 51 cases (1.35%) of de novo T790M mutation and 68 cases (1.81%) of acquired EGFR T790M mutation. Clinical data of the patients were collected for comparative analysis between NSCLC patients with de novo and acquired T790M mutation. Multiple immunofluorescence histochemistry (mIHC) was employed to explore the immune microenvironment characteristics of NSCLC patients with acquired T790M mutation. Results: The proportion of de novo and acquired T790M mutations was higher in female patients compared to males. Patients with de novo T790M mutation tended to be younger. Both de novo and acquired T790M mutations were more commonly found in poorly differentiated carcinomas. Among NSCLC patients with de novo T790M mutation, there was a higher rate of programmed death ligand-1 (PD-L1) expression (60.00%). In contrast, among NSCLC patients with acquired T790M mutation, the rate of PD-L1 expression was lower (22.39%). Acquired T790M mutation in NSCLC was often accompanied by TP53 alterations (39.7%). Cox regression analysis results indicated that mesenchymal to epithelial transition (MET) factor alteration was a risk factor for the occurrence of acquired T790M mutation (P=0.000 5). The average overall survival (OS) showed no significant difference between de novo and acquired T790M mutations (35.4 and 37.3 months respectively). However, patients with acquired T790M mutation exhibited a higher proportion of recurrence and metastasis. In acquired T790M mutation, there was a higher presence of immune cell infiltration within the stromal compartment, such as CD20⁺B cells, CD23⁺ B cells, CD8⁺ T cells, CD8⁺PD-1^-/+ cells, CD20⁺PD-1^-/+ cells and CD23⁺PD-1^-/+ cells. Additionally, the study found that when EGFR was accompanied by tumor suppressor gene (TSG) alterations, the average distance between tumor cells and CD8⁺ T cells, CD20⁺ B cells, CD8⁺PD-1⁺ cells, CD20⁺PD-1⁺ cells and CD23⁺PD-1⁺ cells was closer compared to cases with only EGFR mutations. Conclusion: In comparison to patients with de novo T790M mutation, patients with acquired T790M mutation exhibit a lower rate of PD-L1 positivity. Acquired T790M mutation often accompanies TP53 alterations, and MET alteration is identified as a risk factor triggering acquired T790M mutation. Although patients with acquired T790M mutation face higher risk of recurrence and metastasis, their average OS does not significantly differ from those with de novo T790M mutation. In cases of acquired T790M mutation, the presence of TSG mutations can alter the spatial distribution of immune cells, potentially leading to benefits from immunotherapy.

Key words: Non-small cell lung cancer, EGFR T790M mutation, EGFR TKI, Immune microenvironment