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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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 6

Tumor-vessel normalization following long-term treatment with low-dose therapeutics is highly sustainable.

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Tumor-vessel normalization following long-term treatment with low-dose t...
(A) Eight-week treatment schematic in RIP1-Tag5 mice including 2-week priming and 6-week maintenance phase. (B) Representative images of untreated mice or mice treated with trametinib (0.02 mg/kg), BEZ235 (5 mg/kg), DAPT (5 mg/kg), or anti-VEGFR2 antibodies (V, DC101, 15 mg/kg). FITC-lectin (green) overlay (yellow, arrows) with CD31+ (red) blood vessels was quantified as surrogate marker for tumor perfusion. n = 3–8 mice. Data are represented as mean ± SEM. ****P < 0.0001 for all treatment groups compared with untreated. Quantification of CD31+ intratumoral blood vessels, *P = 0.031, NS, not statistically significant for trametinib, BEZ235, and DAPT treatments compared with untreated, 1-way ANOVA. Scale bar: 100 μm. (C) Representative images and quantification of overlay (yellow, arrows) of CNN1 (red) expressing NG2+ pericytes (green). n = 3–6 mice. Data are represented as mean ± SEM. **P = 0.009; ***P = 0.007; ****P < 0.0001. Quantification of NG2+ intratumoral pericytes: ****P < 0.0001, NS, not statistically significant for trametinib, BEZ235, and DAPT treatments compared with untreated, 1-way ANOVA. Scale bar: 50 μm. (D) Representative H&E images and quantification of percentage of RIP1-Tag5 tumors displaying an intact collagen capsule (dotted line). n = 3–6 mice. Data are represented as mean ± SEM. ****P < 0.0001, NS, not statistically significant for trametinib, BEZ235, and DAPT treatments compared with untreated, 1-way ANOVA. Scale bars: 200 μm (upper images and αVEGFR2); 50 μm (αVEGFR2 detail).