Correlation of MET gene amplification and TP53 mutation with PD-L1 expression in non-small cell lung cancer

Abstract

BackgroundThe role of MET amplification in lung cancer, particularly in relation to checkpoint inhibition and EGFR WT, has not been fully explored. In this study, we correlated PD-L1 expression with MET amplification and EGFR, KRAS, or TP53 mutation in primary lung cancer.MethodsIn this retrospective study, tissue collected from 471 various tumors, including 397 lung cancers, was tested for MET amplification by FISH with a MET/centromere probe. PD-L1 expression was evaluated using clone SP142 and standard immunohistochemistry, and TP53, KRAS, and EGFR mutations were tested using next generation sequencing.ResultsOur results revealed that PD-L1 expression in non-small cell lung cancer is inversely correlated with EGFR mutation (P=0.0003), and positively correlated with TP53 mutation (P=0.0001) and MET amplification (P=0.004). Patients with TP53 mutations had significantly higher MET amplification (P=0.007), and were more likely (P=0.0002) to be EGFR wild type. There was no correlation between KRAS mutation and overall PD-L1 expression, but significant positive correlation between PD-L1 expression and KRAS with TP53 co-mutation (P=0.0002). A cut-off for the ratio of MET: centromere signal was determined as 1.5%, and 4% of lung cancer patients were identified as MET amplified.ConclusionsThis data suggests that in lung cancer both MET and TP53 play direct roles in regulating PD-L1 opposing EGFR. Moreover, KRAS and TP53 co-mutation may cooperate to drive PD-L1 expression in lung cancer. Adding MET or TP53 inhibitors to checkpoint inhibitors may be an attractive combination therapy in patients with lung cancer and MET amplification.

MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1

“…In the present study, high MET expression was associated with high p-GSK3B (Y56), low PDL1 expression, and high granzyme B levels in clinical HCC samples ( Figure 5A and B) with detailed mechanisms ( Figure 5C). Although several studies showed inconsistent correlation between MET amplification and PDL1 expression, 36,37 it is not yet clear whether and how MET directly regulates PDL1 expression in different cell types. Although MET positively correlates with PDL1 in non-small cell lung cancer, 36 the correlation in clear cell renal cell carcinoma seems to be inconsistent.…”

“…Although several studies showed inconsistent correlation between MET amplification and PDL1 expression, 36,37 it is not yet clear whether and how MET directly regulates PDL1 expression in different cell types. Although MET positively correlates with PDL1 in non-small cell lung cancer, 36 the correlation in clear cell renal cell carcinoma seems to be inconsistent. 37 To validate this, we compared the correlation between p-MET and PDL1 in several lung cancer and HCC cell lines.…”

<p>Incidence and PD-L1 Expression of <em>MET</em> 14 Skipping in Chinese Population: A Non-Selective NSCLC Cohort Study Using RNA-Based Sequencing</p>

“…Several recent studies 25,26 reported that PD-L1 expression in NSCLCs is inversely correlated with EGFR mutation and positively correlated with TP53 mutation and MET amplification. The current results also showed that PD-L1 is highly expressed in NSCLC patients with MET exon 14 skipping (69.2% vs 17.3%, P < 0.01), and significantly lower in patients with EGFR mutant cohort (9.3% vs 26.9%, P < 0.01).…”

The Emerging Role of the c-MET-HGF Axis in Non-small Cell Lung Cancer Tumor Immunology and Immunotherapy

“…PD-L1 expression occurs more frequently with MET activation in NSCLC (25), suggesting that besides its well-characterized direct anti-tumor effects inhibition of c-MET signaling may act indirectly to alleviate immunosuppression. Increasing PD-L1 expression correlated positively with MET gene amplification in 389 NSCLC samples (26). A separate study of 155 resected NSCLC tumor samples found MET activation was associated with PD-L1 expression and demonstrated that in NSCLC cell lines c-MET signaling directly induces PD-L1 expression (25).…”