Pericyte Phenotype Switching Alleviates Immunosuppression and Sensitizes Vascularized Tumors to Immunotherapy in Preclinical Models
The efficacy of T cell-based immunotherapies is limited by the immune-suppressive tumor environment mediated by hypoxia, arising from dysfunctional blood vessels. Normalizing the tumor vascular bed can translate into an immune-supportive microenvironment. Here, we show that targeting pericytes to achieve durable vessel normalization can improve immunotherapy outcomes. Specifically, we identified regulator of G protein signaling 5 (RGS5) as a master regulator of tumor pericyte differentiation. Loss of RGS5 function changes the tumor microenvironment by inducing pericyte quiescence and maturity via Rho kinase activation and expression of contractile proteins. The mature pericyte state affords highly sustained vascular changes, which profoundly facilitates anti-tumor immune activity. Importantly, we show that selective low dose therapeutics can induce pericyte maturity and contractility, which mimics genetic RGS5 loss in both mouse and human tumors. Low dose drug therapy durably changes the tumor microenvironment without inducing adaptive resistance, rendering malignant cells more sensitive to immunotherapies. Our findings create a new approach with highly translatable opportunities to improve the outcomes of immune combination therapies. Overall design: Tumors from 27 week-old RIP1-Tag5 mice were harvested and analysed using scRNA-seq.