TY  - JOUR
AU  - Li, Zhi-Jie
AU  - He, Bo
AU  - Domenichini, Alice
AU  - Satiaputra, Jiulia
AU  - Wood, Kira H
AU  - Lakhiani, Devina D
AU  - Bashaw, Abate A
AU  - Nilsson, Lisa M
AU  - Li, Ji
AU  - Bastow, Edward R
AU  - Johansson-Percival, Anna
AU  - Denisenko, Elena
AU  - Forrest, Alistair Rr
AU  - Sakaram, Suraj
AU  - Carretero, Rafael
AU  - Hämmerling, Günter J
AU  - Nilsson, Jonas A
AU  - Lee, Gabriel Yf
AU  - Ganss, Ruth
TI  - Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.
JO  - The journal of clinical investigation
VL  - 134
IS  - 18
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DKFZ-2024-01876
SP  - e179860
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Pericytes: immunology
KW  - Pericytes: metabolism
KW  - Pericytes: pathology
KW  - Mice
KW  - Humans
KW  - Tumor Microenvironment: immunology
KW  - Tumor Microenvironment: drug effects
KW  - Immunotherapy
KW  - Melanoma, Experimental: immunology
KW  - Melanoma, Experimental: therapy
KW  - Melanoma, Experimental: pathology
KW  - Phenotype
KW  - Melanoma: immunology
KW  - Melanoma: therapy
KW  - Melanoma: pathology
KW  - Melanoma: drug therapy
KW  - Cell Line, Tumor
KW  - Immune Tolerance: drug effects
KW  - Cancer immunotherapy (Other)
KW  - Mouse models (Other)
KW  - Oncology (Other)
KW  - Pericytes (Other)
KW  - Therapeutics (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39286984
DO  - DOI:10.1172/JCI179860
UR  - https://inrepo02.dkfz.de/record/293326
ER  -