Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy

Abstract

Renin-angiotensin system (RAS) inhibitors (RASi)-widely prescribed for the treatment of cardiovascular diseases-have considerable potential in oncology. The RAS plays a crucial role in cancer biology and affects tumor growth and dissemination directly and indirectly by remodeling the tumor microenvironment. We review clinical data on the benefit of RASi in primary and metastatic tumors and propose that, by activating immunostimulatory pathways, these inhibitors can enhance immunotherapy of cancer.

Fig. 1

The RAS is a complex system whose bioactive peptides signal through different receptors. Angiotensinogen (AGT), generated and released into circulation by the liver, is hydrolyzed by renin, a product of the kidneys’ juxtaglomerular cells, to form AngI. AngI is then hydrolyzed by ACE, predominantly expressed by endothelial cells in the vascular territory of the lungs, to form the biologically active AngII. In addition to AngII, other truncated bioactive peptides have been identified, such as AngIII, AngIV, Ang(1–7), Ang(1–9), AngA, and alamandine. AngII interacts with two seven-transmembrane receptors, AT1R and AT2R, both of which also mediate the effects of AngA. Ang(1–7) mainly acts via the MAS receptor (MASR), and alamandine binds and signals through MRGD (MAS-related G protein– coupled receptor D). IRAP (insulin-regulated membrane aminopeptidase; also known as AT4R) is a binding site for AngIV (–7). APA, aminopeptidase A; APN, aminopeptidase N; DC, decarboxylase; MLDAD, mononuclear leukocyte-derived aspartate DC; NEP, neutral endopeptidase; PEP, prolyendopeptidase.

Fig. 2

The AngII/AT1R axis regulates the tumor stroma and contributes to an immunosuppressive microenvironment. AngII/AT1R signaling can increase production and release of several proinflammatory cytokines in both tumor and stromal cells. Immunomodulatory cytokines regulate a myriad of immunosuppressive immune responses by modulating differentiation, recruitment, and function of both myeloid and lymphoid immune cell types (4, 43, 44). More precisely, these cytokines suppress the differentiation and function of immunostimulatory cell types [for example, T_H (T helper) and CD8⁺ cells, NK cells, and dendritic cells] and activate recruitment and function of tumor-promoting cell types [such as T_regs, T_H17 cells, TANs, TAMs (tumor-associated macrophages), and MDSCs (myeloid-derived suppressor cells)]. Fibroblasts are a major source of cytokines and also play a key role in establishing a desmoplastic stroma by production and deposition of ECM. The dense tumor fibrosis represents a physical barrier to immune cell infiltration (45) and compresses blood vessels by increasing tissue stiffness and solid stress. The reduced tumor perfusion results in a hypoxic and acidic milieu, which further promotes immunosuppression (–48). Vascular endothelial growth factor (VEGF)–induced vascular leakiness (48) and AngII-mediated vasoconstriction (76, 77, 80) further impair tumor perfusion and aggravate hypoxia. GM-CSF, granulocyte-macrophage colony-stimulating factor. PGE₂, prostaglandin E₂.

Fig. 3

Tumor hypoxia and acidosis promote immunosuppression. AngII/AT1R-mediated effects on tumor vasculature (shown in Fig. 2) can impair tumor perfusion and oxygenation, resulting in hypoxia and acidosis within the tumor stroma. The resulting up-regulation of various cytokines, growth factors, and transcription factors [including HIF (hypoxia-inducible factor), VEGF, and TGF-b] enhances an immunosuppressive microenvironment, characterized by impaired T and dendritic cell function, accumulation of immunosuppressive cell types (M2-like macrophages, MDSCs, and T_regs), and increased expression of inhibitory immune checkpoint molecules such as PD-L1 in tumor and immune cell types (–50, 68). Ang-2, angiopoietin-2; CCL, CC chemokine ligand; CTLA-4, cytotoxic T lymphocyte– associated protein 4; SDF, stromal cell–derived factor.