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

Li, Zhi-Jie1,2,3; He, Bo1,2; Domenichini, Alice1,2; Satiaputra, Jiulia1,2; Wood, Kira H.1,2; Lakhiani, Devina D.1,2; Bashaw, Abate A.2,4; Nilsson, Lisa M.2,4,5,6; Li, Ji1,2; Bastow, Edward R.1,2; Johansson-Percival, Anna1,2; Denisenko, Elena7; Forrest, Alistair R. R.7; Sakaram, Suraj8; Carretero, Rafael9; Haemmerling, Guenter J.10; Nilsson, Jonas A.2,4,5,6; Lee, Gabriel Y. F.11,12; Ganss, Ruth1,2

2024-09-17

10.1172/JCI179860

JOURNAL OF CLINICAL INVESTIGATION   影响因子和分区

0021-9738

1558-8238

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.

SCI

英语

其他

National Health and Medical Research Council (NHMRC)[APP1141847] ; Worldwide Cancer Research[21-0257] ; Cancer Australia["P0411","2002303"] ; Australian NHMRC Fellowship[1154524]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:001318655800010

AMER SOC CLINICAL INVESTIGATION INC

Web of Science

1.Univ Western Australia, Harry Perkins Inst Med Res, QEII Med Ctr, Perth, WA, Australia
2.Univ Western Australia, Ctr Med Res, Perth, WA, Australia
3.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2,Affiliated Hosp 1,Dept Geriatr Med, Shenzhen, Guangdong, Peoples R China
4.Univ Western Australia, Harry Perkins Inst Med Res, QEII Med Ctr, Melanoma Discovery Lab, Perth, WA, Australia
5.Univ Gothenburg, Dept Surg, Inst Clin Sci, Sahlgrenska Ctr Canc Res, Gothenburg, Sweden
6.Sahlgrens Univ Hosp, Gothenburg, Sweden
7.Univ Western Australia, Harry Perkins Inst Med Res, QEII Med Ctr, Syst Biol & Gen Lab, Perth, WA, Australia
8.INSiGENe Ltd, UGenome, Tucson, AZ USA
9.German Canc Res Ctr, DKFZ Bayer Immunotherapeut Lab, Heidelberg, Germany
10.DKFZ, Tumorimmunol Program, Heidelberg, Germany
11.Univ Western Australia, St John God Subiaco Hosp, Perth, WA, Australia
12.Univ Western Australia, Sch Surg, Perth, WA, Australia

Li, Zhi-Jie,He, Bo,Domenichini, Alice,et al. Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models[J]. JOURNAL OF CLINICAL INVESTIGATION,2024,134(18).

Li, Zhi-Jie.,He, Bo.,Domenichini, Alice.,Satiaputra, Jiulia.,Wood, Kira H..,...&Ganss, Ruth.(2024).Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.JOURNAL OF CLINICAL INVESTIGATION,134(18).

Li, Zhi-Jie,et al."Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models".JOURNAL OF CLINICAL INVESTIGATION 134.18(2024).