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

Zhi-Jie Li ^1,2, Bo He ¹, Alice Domenichini ¹

¹Cancer 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.
²Department 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.
³Melanoma 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.
⁴Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
⁵Systems 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.
⁶INSiGENe Ltd., UGenome, Tucson, Arizona, USA.
⁷DKFZ-Bayer Immunotherapeutic Lab, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸Tumorimmunology Program, DKFZ, Heidelberg, Germany.
⁹St. John of God Subiaco Hospital and School of Surgery, The University of Western Australia, Perth, Western Australia, Australia.

⁰Cancer 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.

The Journal of Clinical Investigation +

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September 17, 2024

View abstract on PubMed

Summary

Pericytes regulate tumor oxygenation and immune cell infiltration, enhancing T cell immunotherapy. Inducing pericyte maturity reverses immune suppression and sensitizes tumors to therapy, improving melanoma outcomes.

Area Of Science

Immunology
Oncology
Vascular Biology

Background

T cell-based immunotherapies show promise for cancer treatment but are hindered by tumor hypoxia.
Tumor hypoxia stems from dysfunctional tumor vasculature, impacting immune cell function and therapeutic efficacy.

Purpose Of The Study

To investigate the role of pericytes, a vascular component, in regulating the tumor microenvironment and T cell infiltration.
To determine if modulating pericyte phenotype can enhance the efficacy of adoptive T cell therapy in melanoma.

Main Methods

Studied pericyte phenotype switching (synthetic vs. differentiated) and its impact on tumor oxygenation, macrophage polarization, and T cell infiltration in a mouse melanoma model.
Analyzed pericyte maturity in melanoma patient samples and correlated it with survival outcomes.
Investigated signaling pathways (Rho kinase, MEK, AKT, Notch) regulating pericyte plasticity and tested low-dose therapeutics to induce pericyte differentiation.

Main Results

Pericyte phenotype switching influenced tumor oxygenation, macrophage polarization, and T cell infiltration.
Switching pericytes to a differentiated state reversed immune suppression and sensitized tumors to adoptive T cell therapy, leading to melanoma regression in mice.
Enhanced pericyte maturity in melanoma patients correlated with improved survival.
Pericyte plasticity is regulated by Rho kinase activity and can be modulated by low-dose therapeutics targeting MEK, AKT, or Notch signaling.
Low-dose targeted therapy durably altered the tumor microenvironment without inducing resistance.

Conclusions

Pericytes are critical regulators of the tumor microenvironment and T cell infiltration.
Modulating pericyte phenotype towards a differentiated state enhances anti-tumor immunity and sensitizes tumors to T cell therapy.
Targeting pericyte plasticity with low-dose therapeutics offers a translatable strategy to improve immunotherapy outcomes in cancer patients.

Keywords:

Cancer immunotherapy Mouse models Oncology Pericytes Therapeutics

Related Concept Videos

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.