Elucidation of the relationships of MET protein expression and gene copy number status with PD-L1 expression and the immune microenvironment in non-small cell lung cancer☆
Introduction
Driver oncogenic mutations in genes such as EGFR and ALK are currently considered important therapeutic targets in non-small cell lung cancer (NSCLC) [1,2]. Although driver-specific inhibitors have marked treatment effects on tumors with these driver alterations, tumors often develop resistance [3] and thus become difficult to treat. Recent research on immune-checkpoint inhibitor (ICI) immunotherapy has shed light on intractable cases, and ICI therapy has become one of the first-line treatment options of NSCLC without driver mutations [4]. While ICIs are unlikely to exert satisfactory effects on tumors with driver alterations in EGFR and ALK [5,6], the mechanisms underlying innate resistance caused by these drivers remain unclear. A recent clinical study indicated that platinum-based chemotherapy with atezolizumab was beneficial in patients with EGFR-mutant NSCLC [7]. Therefore, ICI therapy should be personalized based on the driver mutations present in the patient and the context of treatment.
MET is an important oncogene in NSCLC [8,9]. It encodes a tyrosine kinase receptor that activates downstream signaling by binding to its ligand hepatocyte growth factor (HGF), followed by dimerization and auto-phosphorylation [8]. MET overexpression is observed in 25–75 % of NSCLC cases [9], and reportedly predicts worse outcomes in NSCLC [10,11]. Besides activation via HGF, various MET alterations, including gene mutations [8,12,13], fusions [13], and amplification [8,13], cause constitutive MET activation. Among these alterations, high-level MET amplification and MET exon 14 skipping (METex14) mutation have been intensively studied and are regarded as oncogenic drivers in NSCLC [8,12,14]. Both alterations are targeted by MET inhibitors such as crizotinib and cabozantinib [14,15]. The prevalence of de-novo MET amplification in NSCLC ranges from 1 % to 5 % [8,16], depending on the definition of gene amplification and the technology used. In addition, MET amplification is known as a potent and prevalent acquired resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs)—especially to those of the third-generation (observed in 19–30 % of patients) [3,[17], [18], [19]]. Despite being recognized as important oncogenic alterations, compared to that on EGFR mutations, information on how MET alterations are related with tumor PD-L1 expression and the tumor immune microenvironment (TME) is relatively scant [5,6,[20], [21], [22]]. Tumor PD-L1 expression and TME are important factors in understanding treatment mechanisms of ICIs [[23], [24], [25], [26]], and have been suggested as predictive markers of ICI efficacy [27]. There is currently no basis for the efficacy of ICIs in MET-altered tumors. Although recent studies in a small cohort have reported relationships between MET alterations (including altered MET expression) and METex14 and both PD-L1 expression and clinical efficacy of ICIs [[28], [29], [30]], the relationships between MET amplification and the PD-1/PD-L1 axis and TME have not been fully unraveled. Given that MET and EGFR alterations occur in different populations in terms of age, sex, and smoking status [8,12], the relationship between tumors with MET alterations, especially MET amplification, and the PD-L1/PD-1 axis and TME should be urgently characterized.
In this study, we explored the associations between MET alterations, with special focus on MET amplification, and PD-L1 expression and the TME as well as patient characteristics and prognoses in patients with NSCLC. In addition, we described the association between MET alterations and ICI reponse in six patients.
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Patients and tumor specimens
This study was approved by the ethics committees of Hamamatsu University School of Medicine and Seirei Mikatahara General Hospital. All analyses were conducted in compliance with ethical standards and according to the Helsinki Declaration. The need for patient approval and informed consent was waived because this study was based on reviews of patients’ records. We collected 622 NSCLC tumor tissues in total, 406 of which had been resected at Hamamatsu University Hospital between January 1990 and
MET alterations and their mutual associations in NSCLC
In total, 622 NSCLC specimens, comprising 408 (65.6 %) ADCs 169 (27.2 %) squamous cell carcinomas (SCCs), and 45 (7.2 %) tumors with other histologies, were used in this study (Supplementary Table S1). The median age was 68 years (range 23–88 years), and 425 (68.3 %) patients were male. One hundred eighty-four (29.6 %) patients were never-smokers. Regarding pathological stages, there were 392 (63.0 %) stage I, 107 (17.2 %) stage II, and 123 (19.8 %) stage III cases. Two hundred fifty-four (40.8
Discussion
We evaluated relationships between three MET alterations, i.e. MET overexpression, phospho-MET expression, and MET amplification, with PD-L1 expression and four subsets of TILs in the TME of a relatively large NSCLC cohort. The study revealed a strong association between MET overexpression/MET amplification and PD-L1 expression, and indicated that MET amplification, but not MET expression, was independently associated with tumoral CD8 + TILs. Two out of six patients responsive to ICIs had
Data availability
All data and supplementary information within the article are available from the corresponding author upon reasonable request.
Author’s contributions
Study design: K.Y. Study conduct: K.Y. Data collection: K.Y., M.K., H.Y., A.K., M.T., H.O., Data analysis: KY, Y.I. K.T., K.S. Data interpretation: K.Y., K.T., N.I., K.F., H.N., T.S., H.S. Drafting the manuscript: K.Y., Y.I., K.T. Revising the manuscript content: K.Y., Y.I., Y.I., T.K., T.S., H.S. Approving final version of the manuscript: all authors.
Funding
This work was partly supported by grants from the Japanese Ministry of Health, Labor and Welfare (19–19, 10103838), the Japan Society for the Promotion of Science (22590356, 23790396), the Ministry of Education, Culture, Sports, Science and Technology (S-001), the National Cancer Center Research and Development Fund (25-A-1), and Research on Global Health Issues from the Japanese Ministry of Health, Labor and Welfare, Japan Agency for Medical Research and Development (AMED).
Conflicts of interest
The authors declare no competing interests.
Acknowledgments
We thank Mrs. Naoko Yoshida and Mr. Hisaki Igarashi (Hamamatsu University School of Medicine) for technical assistance.
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2022, Lung CancerCitation Excerpt :Kron et al. demonstrated that PD-L1 expression was associated with TP53 mutations in ALK-rearranged lung cancer, but they did not further analyze the PD-L1 expression among different variants and their impact on clinical outcomes [10]. Besides, losses of PTEN and KRAS, as well as MET amplification, have also been reported to induce the PD-L1 expression [41–43]. All of these concomitant mutations could lead to high PD-L1 expression in ALK-rearranged NSCLC and resistance to ALK TKIs.
MET Amplification and Efficacy of Nivolumab in Patients With NSCLC
2021, JTO Clinical and Research ReportsCitation Excerpt :Then, the ratio of the mean targeted signal to the mean centromere enumeration probe (CEP) 7 signal (MET/CEP7) was determined. MET amplification was primarily defined as having an average MET-to-CEP7 ratio of greater than or equal to 2.0 per nucleus.15,21,22 In accordance with previous publications, we have also applied the secondary definition for MET copy number status, which categorizes MET gene status into the following three groups by average MET copy numbers/nucleus23,24: high-level MET gain (MET signals ≥10), low-level MET gain (10> MET signals ≥5), and no MET gain (5> MET signals).
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Notification of prior presentation: The data in this article were presented at the Oral session at the 60th Annual Meeting of the Lung Cancer Society, December 6, 2019, Tokyo, Japan.