Suppression of tumor immune microenvironment via microRNA-1 after epidermal growth factor receptor-tyrosine kinase inhibitor resistance acquirement in lung adenocarcinoma.

Immunotherapy is considered one of the most important therapeutic strategies for patients with lung adenocarcinoma after the development of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. However, useful predictors of immunotherapy for these patients has not been examined well, although the status of the tumor immune microenvironment (TIME), including programmed death-ligand 1 expression and lymphocyte infiltration, has been generally known to provide predictive markers for the efficacy of immunotherapy. This study aimed to clarify novel predictors of immunotherapy following EGFR-TKI resistance in lung adenocarcinoma, especially regarding micro RNA (miRNA). We evaluated the correlation between EGFR-TKI resistance and lymphocyte infiltration, before and after acquiring EGFR-TKI resistance, in 21 cases of lung adenocarcinoma, and further explored this by in vitro studies, using miRNA PCR arrays. Subsequently, we transfected miRNA-1 (miR-1), the most variable miRNA in this array, into three kinds of lung cancer cells, and examined the effects of miR-1 on EGFR-TKI sensitivity, cytokine expression and lymphocyte migration. Histopathological examination demonstrated that infiltration levels of CD8-positive T cells were significantly decreased after development of EGFR-TKI resistance. In vitro studies revealed that miR-1 significantly inhibited EGFR-TKI effect and induction of cytokines, such as C-C motif chemokine ligand 5 and C-X-C motif chemokine ligand 10, causing inhibition of monocyte migration. These results indicate that the upregulated miR-1 might suppress the TIME, following development of EGFR-TKI resistance. Therefore, miR-1 could be a clinically useful marker to predict therapeutic efficacy of immunotherapy in lung adenocarcinoma patients with EGFR-TKI resistance.

Kawana S ，Saito R ，Miki Y ，Kimura Y ，Abe J ，Sato I ，Endo M ，Sugawara S ，Sasano H ... -  《Cancer Medicine》

[Immune Microenvironment Comparation Study between EGFR Mutant and EGFR Wild Type Lung Adenocarcinoma Patients Based on TCGA Database].

Zhu G ，Li Y ，Shi R ，Xu S ，Zhang Z ，Cao P ，Chen C ，Liu H ，Chen J ... -  《-》

Association between programmed death-ligand 1 expression, immune microenvironments, and clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients treated with tyrosine kinase inhibitors.

Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression. Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments. A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression <50% (ORR/PFS in PD-L1 0% versus 1-49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P < 0.05). The multivariate analysis showed that PD-L1 <50% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250-0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1-49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses. Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.

Yang CY ，Liao WY ，Ho CC ，Chen KY ，Tsai TH ，Hsu CL ，Su KY ，Chang YL ，Wu CT ，Hsu CC ，Liao BC ，Hsu WH ，Lee JH ，Lin CC ，Shih JY ，Yang JC ，Yu CJ ... -  《-》

Suppression of Mig-6 overcomes the acquired EGFR-TKI resistance of lung adenocarcinoma.

Kang DH ，Jung SS ，Yeo MK ，Lee DH ，Yoo G ，Cho SY ，Oh IJ ，Kim JO ，Park HS ，Chung C ，Lee JE ... -  《BMC CANCER》

MiR-200c-3p suppression is associated with development of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer via a mediating epithelial-to-mesenchymal transition (EMT) proces

Wang HY ，Liu YN ，Wu SG ，Hsu CL ，Chang TH ，Tsai MF ，Lin YT ，Shih JY ... -  《-》