Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models
Zhi-Jie Li, … , Gabriel Y.F. Lee, Ruth Ganss
Zhi-Jie Li, … , Gabriel Y.F. Lee, Ruth Ganss
Published September 17, 2024
Citation Information: J Clin Invest. 2024;134(18):e179860. https://doi.org/10.1172/JCI179860.
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Research Article Oncology

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

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.

Authors

Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H. Wood, Devina D. Lakhiani, Abate A. Bashaw, Lisa M. Nilsson, Ji Li, Edward R. Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair R.R. Forrest, Suraj Sakaram, Rafael Carretero, Günter J. Hämmerling, Jonas A. Nilsson, Gabriel Y.F. Lee, Ruth Ganss

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Figure 2

Intratumoral RGS5 expression determines pericyte phenotype in vivo and blood vessel functionality.

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Intratumoral RGS5 expression determines pericyte phenotype in vivo and b...
(A) PNET from WT RIP1-Tag5 (WT), RIP1-Tag5 on a Rgs5-knockout background (Rgs5KO or KO), and triple-transgenic RIP1-Tag5 × UbiCRGS5 × RGS5CreERT2 mice engineered to overexpress RGS5 (Rgs5hi or HI) were analyzed at 27 weeks. Images depict vascular CD31 expression (red) and infused FITC-lectin (green) as surrogate markers for tumor perfusion; arrows indicate overlay (yellow). Quantification of overlay and CD31 vessel area. n = 3–4 mice. *P = 0.02; ****P < 0.0001, 1-way ANOVA. (B) Extravasation of 70 kD dextran (red, arrowheads) from blood vessels into tumor parenchyma as marker for vessel leakiness. n = 3 mice. Data are represented as mean ± SEM. *P = 0.04; **P = 0.0014, 1-way ANOVA. (C) Calponin (CNN1, red) expression in pericytes (NG2, green); arrows indicate overlay (yellow); quantification of overlay and frequency of NG2+ pericytes. n = 5 mice, *P = 0.0064; **P = 0.0008; ***P < 0.0001, 1-way ANOVA. (D) COLI (red) deposition around pericytes (ACTA2, green); brackets indicate width of COLI deposits. n = 3–5 mice. Data are represented as mean ± SEM. *P = 0.022; ***P = 0.0006; ****P < 0.0001, 1-way ANOVA. (E) VE-cadherin (CDH5, red, arrowheads) coverage of CD31 (blue) vessels, n = 4–5 mice. Data are represented as mean ± SEM. **P = 0.0023; ***P < 0.0001, 1-way ANOVA. (F) p-MLC (red) expression in pericytes (NG2, green); arrows indicate overlay (yellow), n = 3–4 mice. Data are represented as mean ± SEM. *P = 0.03; **P = 0.0003; ***P < 0.0001, 1-way ANOVA. (G) Fasudil treatment schematic of Rgs5KO PNET mice and assessment of tumor perfusion at endpoint. CD31 (red) overlay with infused FITC-lectin (yellow) is highlighted by arrows. Perfusion was quantified in Rgs5KO+fasudil (F) group in comparison with WT and Rgs5KO (data from A, shadowed). n = 4–5 mice. Data are represented as mean ± SEM. ****P < 0.0001, 1-way ANOVA. Scale bars: 50 μm (A–D, F, G); 25 μm (E).