Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.

Autor: Li ZJ; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.; Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China., He B; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Domenichini A; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Satiaputra J; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Wood KH; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Lakhiani DD; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Bashaw AA; Melanoma Discovery Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Nilsson LM; Melanoma Discovery Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.; Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden., Li J; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Bastow ER; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Johansson-Percival A; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Denisenko E; Systems Biology and Genomics Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Forrest AR; Systems Biology and Genomics Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia., Sakaram S; INSiGENe Ltd., UGenome, Tucson, Arizona, USA., Carretero R; DKFZ-Bayer Immunotherapeutic Lab, German Cancer Research Center (DKFZ), Heidelberg, Germany., Hämmerling GJ; Tumorimmunology Program, DKFZ, Heidelberg, Germany., Nilsson JA; Melanoma Discovery Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.; Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden., Lee GY; St. John of God Subiaco Hospital and School of Surgery, The University of Western Australia, Perth, Western Australia, Australia., Ganss R; Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Sep 17; Vol. 134 (18). Date of Electronic Publication: 2024 Sep 17.
DOI: 10.1172/JCI179860
Abstrakt: T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.
Databáze: MEDLINE