Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

Abstract

Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.

Conflict of interest statement

Competing interests

D.G.D. has received consultancy fees from Bayer and research funding from Bayer, Bristol-Myers Squibb, Exelixis, Leap, and Merrimack. R.K.J. has received consultancy fees from Merck, Ophthotech, Pfizer, SPARC, and SynDevRx; owns equity in Enlight, Ophthotech, SynDevRx, and XTuit; and serves on the board of directors of XTuit and the boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. D.F., Z.A., and J.K. do not have any conflicts of interest to declare.

Figures

Figure 1. Direct effects of angiogenic factors on various immune cells

VEGF and other angiogenic factors, such as angiopoietin 2 (ANG2), modulate the functions of innate and adaptive immune cells towards immunosuppression. VEGF can be produced by tumour cells and immune cells (red stars) as well as by endothelial cells and stromal cells. VEGF creates a pro-tumour microenvironment by increasing the number and enhancing the suppressive functions of regulatory T (Treg) cells and tumour-associated macrophages (TAMs) and/or monocytes. These cell populations also produce VEGF (red stars) and ANG2 (green pentagons) and thereby engage in paracrine and autocrine VEGF (and/or ANG2) signalling. Among immune cells, Treg cells have been identified as the major source of VEGF in the tumour microenvironment using in vivo models. This finding was further confirmed in a different study. While VEGF directly inhibits the development and/or activation of cytotoxic T lymphocytes (CTLs), CTL-produced VEGF can induce angiogenesis and promote tumour progression. Furthermore, VEGF has been shown to increase the numbers of CD4+ memory T cells (Supplementary Table S4). VEGF can promote the expansion of myeloid-derived suppressor cells (MDSCs) and improve their immunosuppressive function in the tumour microenvironment (TME). Importantly, dendritic cells (DCs), which are required for priming of CTLs, lose their ability to mature and present antigens following VEGF exposure in vitro. Consequently, the anticancer activity of CTLs in the TME might be compromised. In this context, CTLs have a decreased capacity to traffic to the tumour, proliferate, and produce cytokines that are integral to the anticancer immune response, such as IFNγ and tumour necrosis factor. Collectively, Treg cells, TAMs, MDSCs, and immature DCs suppress the activity of CTLs, resulting in a pro-tumour microenvironment. The roles of ANG2 (and ANG1) in modulating various immune cells are not as well understood as those of VEGF; thus, the effects of ANG2 are not illustrated in this figure.

Figure 2. The abnormal tumour vasculature contributes to immunosuppression in the tumour microenvironment

Abnormalities in the tumour vasculature result in hypoxia and acidosis of the tumour microenvironment (TME), which in turn contribute to immunosuppression via several mechanisms. These mechanisms include increased accumulation, activation, and expansion of immunosuppressive regulatory T (Treg) cells; recruitment of inflammatory monocytes and tumour-associated macrophages (TAMs) and reprogramming of TAMs from an anticancer M1-like phenotype towards the pro-tumour M2 phenotype; suppression of dendritic cell (DC) maturation, which results in impaired antigen presentation and activation of tumour-specific cytotoxic T lymphocytes (CTLs); and expansion of abnormal endothelial cells (ECs) with immunosuppressive phenotypes. Importantly, the programmed cell death protein 1 (PD-1)–programmed cell death 1 ligand 1 (PD-L1) pathway is often activated in the TME as a mechanism to evade anticancer immune responses, with upregulation of PD-L1 expression on TAMs, DCs, and ECs, as well as on tumour cells. In addition, tumour-infiltrating CTLs typically upregulate PD-1, marking them as dysfunctional or ‘exhausted’ and limiting their cytotoxic potential against tumour cells. Overall, the consequence of aberrant tumour angiogenesis and vascular abnormality is an immunosuppressive TME. ANG2, angiopoietin 2; CCL, C-C-motif chemokine ligand; CXCL12, C-X-C-motif chemokine ligand 12; CSF1, macrophage colony-stimulating factor 1; FASL, FAS antigen ligand; GM-CSF, granulocyte–macrophage colony-stimulating factor; TGFβ, transforming growth factor β.

Figure 3. Tumours secrete factors that cause systemic immunosuppression

The cells of the tumour microenvironment exert systemic immunosuppressive effects by releasing factors such as VEGF, transforming growth factor β (TGFβ), and prostaglandin E2 (PGE2) into the circulation. Collectively, these cytokines reduce the ability of antigen-presenting cells to prime T cells and thus reduce the anticancer responses of effector T cells. In addition, tumour-derived factors increase the presence and function of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells, which suppress anticancer immunity.

Figure 4. Vascular-normalizing therapies can reprogramme the immunosuppressive tumour microenvironment to an immunosupportive one

The structural and functional abnormalities of tumour blood vessels lead to impaired blood flow and perfusion, thus resulting in a hypoxic tumour microenvironment (TME). Hypoxic conditions in tumours limit the effectiveness of cytotoxic therapies, such as radiation therapy and certain chemotherapies. In addition, drug delivery to the tumour via these abnormal vessels is impaired, and this problem is further exacerbated by the high interstitial fluid pressure — a consequence of the leaky blood vessels and irregular lymphatic system in the tumour. Moreover, abnormal and leaky tumour blood vessels facilitate the intravasation of cancer cells into the systemic circulation, promoting metastasis. Furthermore, the abnormal TME is associated with increased infiltration of immunosuppressive regulatory T cells and polarizes tumour-associated macrophages from an anticancer M1-like phenotype towards an immunosuppressive M2 phenotype. The dysfunctional vasculature also restricts the accumulation and homogeneous intratumoural distribution of effector T cells. Consequently, anticancer immune responses are severely impaired. Vascular normalization could potentially prevent or reverse many of these adverse effects in patients, enhance the delivery and effectiveness of chemotherapy and immunotherapy, and improve the anticancer effects of radiotherapy.