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

• Published in: The Journal of clinical investigation 2024-09, Vol.134 (18), p.1-18
• Main Authors: Li, Zhi-Jie, He, Bo, Domenichini, Alice, Satiaputra, Jiulia, Wood, Kira H, Lakhiani, Devina D, Bashaw, Abate A, Nilsson, Lisa M, Li, Ji, Bastow, Edward R, Johansson-Percival, Anna, Denisenko, Elena, Forrest, Alistair Rr, Sakaram, Suraj, Carretero, Rafael, Hämmerling, Günter J, Nilsson, Jonas A, Lee, Gabriel Yf, Ganss, Ruth
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Blood vessels; Cancer; Cancer and Oncology; Cancer immunotherapy; Cancer och onkologi; Cancer therapies; Care and treatment; Cell culture; Cell differentiation; Cell Line, Tumor; Cell therapy; Cells; Clinical trials; Drug therapy; Endothelium; Genetic aspects; Genotype & phenotype; Health aspects; Humans; Hypoxia; Immune Tolerance - drug effects; Immunosuppression; Immunotherapy; Kinases; Lymphocytes; Lymphocytes T; Macrophages; Malignancy; Medical research; Medicine, Experimental; Melanoma; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Metastases; Metastasis; Mice; Mouse models; Oncology; Pericytes; Pericytes - immunology; Pericytes - metabolism; Pericytes - pathology; Phenotype; Phenotypes; Phenotypic plasticity; Physiological aspects; Proteins; Rho-associated kinase; Scientific equipment and supplies industry; Signal transduction; Smooth muscle; T cells; Therapeutics; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI179860

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.