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2024

J Clin Invest. 2024 Sep 17;134(18):e179860. doi: 10.1172/JCI179860.

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

Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H Wood, Devina D Lakhiani, Abate A Bashaw, Lisa M Nilsson, Ji Li, Edward R Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair Rr Forrest, Suraj Sakaram, Rafael Carretero, Günter J Hämmerling, Jonas A Nilsson, Gabriel Yf Lee, Ruth Ganss

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. 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. 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. INSiGENe Ltd., UGenome, Tucson, Arizona, USA. DKFZ-Bayer Immunotherapeutic Lab, German Cancer Research Center (DKFZ), Heidelberg, Germany. Tumorimmunology Program, DKFZ, Heidelberg, Germany. St. John of God Subiaco Hospital and School of Surgery, The University of Western Australia, Perth, Western Australia, Australia.

Service type: Knock-in mice

Abstract

Abstract 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.

Keywords: Cancer immunotherapy; Mouse models; Oncology; Pericytes; Therapeutics.

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