Journal Article

DKFZ-2024-01876

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.

Li, Z.-J. ; He, B. ; Domenichini, A. ; Satiaputra, J. ; Wood, K. H. ; Lakhiani, D. D. ; Bashaw, A. A. ; Nilsson, L. M. ; Li, J. ; Bastow, E. R. ; Johansson-Percival, A. ; Denisenko, E. ; Forrest, A. R. ; Sakaram, S. ; Carretero, R.DKFZ* ; Hämmerling, G. J.DKFZ* ; Nilsson, J. A. ; Lee, G. Y. ; Ganss, R.

2024
ASCJ Ann Arbor, Mich.

This record in other databases:  

Please use a persistent id in citations: doi:10.1172/JCI179860

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.

Keyword(s): Animals (MeSH) ; Pericytes: immunology (MeSH) ; Pericytes: metabolism (MeSH) ; Pericytes: pathology (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Tumor Microenvironment: immunology (MeSH) ; Tumor Microenvironment: drug effects (MeSH) ; Immunotherapy (MeSH) ; Melanoma, Experimental: immunology (MeSH) ; Melanoma, Experimental: therapy (MeSH) ; Melanoma, Experimental: pathology (MeSH) ; Phenotype (MeSH) ; Melanoma: immunology (MeSH) ; Melanoma: therapy (MeSH) ; Melanoma: pathology (MeSH) ; Melanoma: drug therapy (MeSH) ; Cell Line, Tumor (MeSH) ; Immune Tolerance: drug effects (MeSH) ; Cancer immunotherapy ; Mouse models ; Oncology ; Pericytes ; Therapeutics

---

Contributing Institute(s):

1. DKFZ -Bayer Healthcare Joint (D220)
2. KKE Angewandte Tumorbiologie (D470)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2024

---

Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---