Trimming the Vascular Tree in Tumors: Metabolic and Immune Adaptations

Abstract

Angiogenesis, the formation of new blood vessels, has become a well-established hallmark of cancer. Its functional importance for the manifestation and progression of tumors has been further validated by the beneficial therapeutic effects of angiogenesis inhibitors, most notably ones targeting the vascular endothelial growth factor (VEGF) signaling pathways. However, with the transient and short-lived nature of the patient response, it has become evident that tumors have the ability to adapt to the pressures of vascular growth restriction. Several escape mechanisms have been described that adapt tumors to therapy-induced low-oxygen tension by either reinstating tumor growth by vascular rebound or by altering tumor behavior without the necessity to reinitiate revascularization. We review here two bypass mechanisms that either instigate angiogenic and immune-suppressive polarization of intratumoral innate immune cells to facilitate VEGF-independent angiogenesis or enable metabolic adaptation and reprogramming of endothelial cells and tumor cells to adapt to low-oxygen tension.

Figure 1.

(A) Tumors responsive to antiangiogenic inhibition (AI) are infiltrated by Th2-type myeloid cells, which promote an immunosuppressive and proangiogenic phenotype. Treatment with antiangiogenic therapy leads to reduced vessel density and increased hypoxia, and cytokine release transiently shifts the population to a Th1 immune-stimulatory/angiostatic phenotype, leading to cytotoxic T-lymphocyte (CTL) influx, increased apoptosis, and tumor stasis/reduction. Activation of phosphoinositide 3-kinase γ (PI3Kγ) in myeloid cells repolarizes the immune population back to a Th2* phenotype that is now highly immune suppressive and angiogenic and unresponsive to continued antiangiogenic inhibition, leading to vascular rebound and regrowth. RTK, receptor tyrosine kinase; TLR, Toll-like receptor; GPCR, Gαi protein-coupled receptor. (B) AI-resistant tumors consist of PI3Kγ-independent, immune suppressive, and angiogenic Th2 cells (orange), and PI3Kγ-dependent, highly immune-suppressive, and angiogenic Th2* cells (red). Single AI treatment results in a shift of Th2 cells to the angiostatic and immune stimulatory Th1 cells (blue), creating an intermediate response. In addition, single PI3Kγ inhibitor treatment shifted Th2* to Th1 cells, leaving the Th2 cell population unaffected and also producing an intermediate response. In contrast, combination AI/PI3Kγ inhibition stimulated a shift of Th2 cells to Th1 cells and eradicated the highly immune-suppressive and angiogenic Th2* cells. This treatment produces an angiostatic and immune-stimulatory effect, resulting in an enhanced response.

Figure 2.

Schematic representation of angiogenesis inhibitor (AI)-induced metabolic symbiosis and the effect of mammalian target of rapamycin (mTOR) inhibition. (Left) Treatment with an AI causes vascular collapse to produce normoxic, hypoxic, and necrotic regions, based on their proximity to functional blood vessels. (Middle, mTOR”on.”) Tumor cells in hypoxic regions up-regulate expression of the glucose transporter GLUT1, increase glycolysis, and export lactate via MCT4. In parallel, mTOR-expressing normoxic tumor cells spare glucose and import lactate via MCT1 to fuel O₂-dependent oxidative phosphorylation (OxPHOs). (Right, mTOR”off”) Disruption of symbiosis via mTOR inhibition disrupts lactate catabolism in normoxic cells, which can produce increased intracellular lactate concentrations, reduced extracellular lactate clearance, and increased acidosis. Furthermore, mTOR inhibition up-regulates GLUT2 expression in normoxic cells, which can increase glucose consumption by the normoxic cells to reduce its availability for the hypoxic compartment.