Katsuhiro Yoshimura1, Yusuke Inoue1, Kazuo Tsuchiya1, Masato Karayama2, Hidetaka Yamada3, Yuji Iwashita3, Akikazu Kawase4, Masayuki Tanahashi5, Hiroshi Ogawa6, Naoki Inui7, Kazuhito Funai4, Kazuya Shinmura3, Hiroshi Niwa5, Takafumi Suda2, Haruhiko Sugimura8. 1. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan. 2. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan. 3. Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan. 4. First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan. 5. Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan. 6. Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, Japan. 7. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan. 8. Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: hsugimur@hama-med.ac.jp.
Abstract
OBJECTIVES: Alterations in the MET gene, such as mutations and high-level amplification, are important drivers of non-small cell lung cancer (NSCLC). The efficacy of immune checkpoint inhibitors (ICIs) in lung cancer with MET abnormalities is unclear. We evaluate the potential relationship between MET alterations and the tumor immune microenvironment and PD-1/PD-L1 axis. MATERIAL AND METHODS: MET and phospho-MET protein expression were assessed in 622 resected NSCLC specimens. MET amplification was assessed by fluorescence in-situ hybridization in 272 tumors. PD-L1 expression was evaluated by immunohistochemistry. CD8+, Foxp3+, CD45RO, and PD-1+ tumor-infiltrating lymphocytes (TILs) in the tumor nest and surrounding stroma were profiled. Associations with MET alterations were explored. RESULTS: The cohort comprised 425 male patients (68.3 %), 184 never-smokers (29.6 %), and 408 adenocarcinoma (ADC) patients (65.6 %). Median age was 68 years. MET alteration was observed mainly in ADCs (18.9 % MET-positive, 3.9 % phospho-MET-positive, and 15.1 % with MET amplification). PD-L1 expression was significantly increased in MET-altered ADCs (P < 0.001 for MET; P = 0.002 for phospho-MET; P = 0.019 for MET amplification). Most TIL subset numbers in the tumor nest were significantly increased in MET-altered tumors. Only MET amplification was independently associated with tumoral CD8 + TILs. Three of the six patients responded to ICI treatment; two of them showed MET overexpression and an increase in MET copy number. CONCLUSION: MET-altered tumors showed significantly stronger PD-L1 expression and more abundant tumoral TILs than non-MET-altered tumors. Among the MET alterations assessed, MET amplification was particularly implicated in the inflamed microenvironment, suggesting that MET-amplified tumors might respond to ICIs.
OBJECTIVES: Alterations in the MET gene, such as mutations and high-level amplification, are important drivers of non-small cell lung cancer (NSCLC). The efficacy of immune checkpoint inhibitors (ICIs) in lung cancer with MET abnormalities is unclear. We evaluate the potential relationship between MET alterations and the tumor immune microenvironment and PD-1/PD-L1 axis. MATERIAL AND METHODS: MET and phospho-MET protein expression were assessed in 622 resected NSCLC specimens. MET amplification was assessed by fluorescence in-situ hybridization in 272 tumors. PD-L1 expression was evaluated by immunohistochemistry. CD8+, Foxp3+, CD45RO, and PD-1+ tumor-infiltrating lymphocytes (TILs) in the tumor nest and surrounding stroma were profiled. Associations with MET alterations were explored. RESULTS: The cohort comprised 425 male patients (68.3 %), 184 never-smokers (29.6 %), and 408 adenocarcinoma (ADC) patients (65.6 %). Median age was 68 years. MET alteration was observed mainly in ADCs (18.9 % MET-positive, 3.9 % phospho-MET-positive, and 15.1 % with MET amplification). PD-L1 expression was significantly increased in MET-altered ADCs (P < 0.001 for MET; P = 0.002 for phospho-MET; P = 0.019 for MET amplification). Most TIL subset numbers in the tumor nest were significantly increased in MET-altered tumors. Only MET amplification was independently associated with tumoralCD8 + TILs. Three of the six patients responded to ICI treatment; two of them showed MET overexpression and an increase in MET copy number. CONCLUSION: MET-altered tumors showed significantly stronger PD-L1 expression and more abundant tumoral TILs than non-MET-altered tumors. Among the MET alterations assessed, MET amplification was particularly implicated in the inflamed microenvironment, suggesting that MET-amplified tumors might respond to ICIs.
Authors: Alessa Fischer; Lorenz Bankel; Stefanie Hiltbrunner; Markus Rechsteiner; Jan H Rüschoff; Elisabeth Jane Rushing; Christian Britschgi; Alessandra Curioni-Fontecedro Journal: Target Oncol Date: 2022-09-22 Impact factor: 4.864