Projects per year
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.
Original language | English |
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Article number | e179860 |
Number of pages | 19 |
Journal | Journal of Clinical Investigation |
Volume | 134 |
Issue number | 18 |
DOIs | |
Publication status | Published - 17 Sept 2024 |
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Dive into the research topics of 'Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models'. Together they form a unique fingerprint.Projects
- 2 Finished
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Systems Biology of Human Disease
NHMRC National Health and Medical Research Council
1/01/19 → 31/12/23
Project: Research
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Small molecule inhibitors to reprogram the tumour environment and improve immunotherapy
Ganss, R. & Hammerling, G.
NHMRC National Health and Medical Research Council
1/01/18 → 31/12/21
Project: Research