Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis1,2. Vessel normalization (VN) may resolve this paradox3. VN involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia3. While these processes alter tumour progression, their regulation is poorly understood. Here we show that Type 1 T helper (Th1) cells play a crucial role in VN. Bioinformatic analyses revealed that gene expression features related to VN correlate with immunostimulatory pathways, especially T lymphocyte (TL) infiltration/activities. To delineate the causal relationship, we employed various mouse models with VN or TL deficiencies. While VN disruption reduced TL infiltration as expected4, reciprocal depletion or inactivation of CD4+-TLs decreased VN, indicating a mutually-regulatory loop. Additionally, CD4+-TL activation by immune checkpoint blockade (ICB) increased VN. IFNγ+ Th1 cells are the major population associated with VN. Patient-derived xenograft (PDX) tumours growing in immunodeficient animal hosts exhibited enhanced hypoxia compared to the original tumours in immunocompetent human hosts, which was reduced by adoptive Th1 transfer. Our findings elucidate an unexpected role of Th1 in vasculature and immune reprogramming. Th1 cells may be a marker and a determinant of both ICB and anti-angiogenesis efficacies.

Endothelial cells in growing tumors express activated Akt, which when modeled by transgenic endothelial expression of myrAkt1 was sufficient to recapitulate the abnormal structural and functional features of tumor blood vessels in nontumor tissues. Sustained endothelial Akt activation caused increased blood vessel size and generalized edema from chronic vascular permeability, while acute permeability in response to VEGF-A was unaffected. These changes were reversible, demonstrating an ongoing requirement for Akt signaling for the maintenance of these phenotypes. Furthermore, rapamycin inhibited endothelial Akt signaling, vascular changes from myrAkt1, tumor growth, and tumor vascular permeability. Akt signaling in the tumor vascular stroma was sensitive to rapamycin, suggesting that rapamycin may affect tumor growth in part by acting as a vascular Akt inhibitor.

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We investigated the functions of Akt during vascular development and remodeling by using an inducible endothelial cell-specific driver of the dominant-active myrAkt. We found that sustained signaling in response to overexpression of myrAkt led to embryonic lethality, edema, and vascular malformations. In addition to the morphological malformations, the vascular phenotype was consistent with a failure in remodeling, such that the normal patterning and vessel hierarchy was disturbed. Examination of the well studied retinal vasculature during the remodeling phases revealed that transient expression of myrAkt was capable of altering the normal response to oxygen-induced remodeling without causing vascular malformations. These findings suggest that physiological levels of Akt signaling modulated microvascular remodeling and support the hypothesis that, although Akt may be required for vascular growth and homeostasis, appropriate downregulation is also an essential aspect of normal vascular patterning.Akt͞PKB ͉ angiogenesis ͉ retina E ndothelial cell survival and apoptosis have been studied extensively with respect to micro-and macrovascular disease in diabetes, cardiovascular disease, sepsis, and after transplant surgery (1). As a desired effect of therapy, endothelial cell apoptosis has been explored in response to antiangiogenic treatments for cancer (2). Less attention has been paid to the control of endothelial cell apoptosis during development, although it has been proposed to explain the overall decrease in microvascular density associated with microvascular remodeling.Much of the classical work on microvascular remodeling has been done in the developing retina because of its planar architecture and accessibility, because the expansion and remodeling of this vascular bed is postnatal. A series of elegant studies have clearly established VEGF-A as a driver of vascular expansion in this organ in both development (3, 4) and pathological neovascularization (5-7) as well as a regulator of endothelial cell survival during the remodeling process (8). In the retina, VEGF-A is provided largely by the astrocytes, which enter the retina through the optic disk and spread radially toward the periphery in advance of blood vessel formation (3, 9). The astrocytes are exquisitely sensitive to oxygen levels and strongly induce VEGF-A in hypoxic regions of the retina (10, 11). As the astrocytes and expand radially across the retina, they attract the endothelium to follow and lay a scaffold on which blood vessels form, in part due to the molecular attraction of VEGFR-2 expressed on endothelial cell filopodia with sequestered VEGF on the astrocyte surface (9). Once the new blood vessels bring oxygen to the formerly hypoxic regions of the retina, local VEGF-A levels drop. These events initiate the remodeling process where vessel regression is coordinated with pericyteinduced stabilization (12,13). This coordination of oxygeninduced VEGF-A reduction and pericyte stabilization has led to the hypothesis that the balance in survival sig...