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 4

Low-dose therapeutics mimic Rgs5 knockdown by inducing pericyte maturation.

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Low-dose therapeutics mimic Rgs5 knockdown by inducing pericyte maturati...
(A) RGS5 signaling and Rho kinase–activating effects of inhibitors (blue bars). (B) Relative RGS5 expression in 10T1/2 cells, 40 μM DAPT. n = 3 biological replica. Data are represented as mean ± SEM. ***P = 0.0001, Student’s t test. (C) Relative RGS5 expression in RIP1-Tag5 tumors treated with DAPT. n = 7–8 mice. Data are represented as mean ± SEM. *P = 0.025, Student’s t test. (D) Contractile markers (CNN1, ACTG2) and p-MLC in RGS5myc cells with increasing doses of trametinib. Quantification of 3 independent experiments. Data are represented as mean ± SEM. *P ≤ 0.04, **P ≤ 0.006, 1-way ANOVA (Kruskal-Wallis test). (E) Representative WB of CNN1, ACTG2, and p-MLC in RGS5myc cells with increasing doses of BEZ235 (left) and DAPT (right). The experiment was conducted twice. (F) RIP1-Tag5 mice untreated (U) or treated with trametinib (T), BEZ235 (B), or DAPT (D). FITC-lectin overlay (yellow) with CD31+ (red) vessels was quantified. n = 4–12. Data are represented as mean ± SEM. *P = 0.0173; **P = 0.0001; ***P < 0.0001, 1-way ANOVA. (G) Quantification of CNN1 expression (red) in relation to NG2+ pericytes (green). Arrows indicate overlay (yellow), n = 6–8. Data are represented as mean ± SEM. *P = 0.022, ***P < 0.0001, 1-way ANOVA. (H) COLI deposition (red) around NG2+ pericytes (green). Arrows indicate overlay of markers (yellow). n = 6–12. Data are represented as mean ± SEM. *P = 0.006; **P = 0.0006; ***P = 0.0005, 1-way ANOVA. (I) p-MLC expression in NG2+ pericytes (green). Arrows indicate overlay (yellow). n = 4–7. Data are represented as mean ± SEM. *P = 0.016; **P = 0.014; ***P = 0.0053, 1-way ANOVA. Scale bars: 100 μm (F); 50 μm (G–I).