Kyohei Hakozaki1, Nobuyuki Tanaka2, Kimiharu Takamatsu1, Ryohei Takahashi1, Yota Yasumizu1, Shuji Mikami3, Toshiaki Shinojima1,4, Kazuhiro Kakimi5, Takashi Kamatani6,7,8, Fuyuki Miya7, Tatsuhiko Tsunoda6,7,9, Eriko Aimono10, Hiroshi Nishihara10, Ryuichi Mizuno1, Mototsugu Oya1. 1. Department of Urology, Keio University School of Medicine, 160-8582, Tokyo, Japan. 2. Department of Urology, Keio University School of Medicine, 160-8582, Tokyo, Japan. urotanaka@keio.jp. 3. Department of Diagnostic Pathology, Keio University Hospital, Tokyo, Japan. 4. Department of Urology, Saitama Medical University, Moroyama, Saitama, Japan. 5. Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan. 6. Laboratory for Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan. 7. Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 8. Department of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan. 9. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 10. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
Abstract
BACKGROUND: Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis. METHODS: To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays. RESULTS: Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC. CONCLUSION: The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.
BACKGROUND: Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis. METHODS: To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays. RESULTS: Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC. CONCLUSION: The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.
Authors: Agnete S T Engelsen; Maria L Lotsberg; Raefa Abou Khouzam; Jean-Paul Thiery; James B Lorens; Salem Chouaib; Stéphane Terry Journal: Front Immunol Date: 2022-04-27 Impact factor: 8.786