The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

Abstract

Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

Keywords: angiogenesis inhibitors; endothelial cells; immunotherapy; lymphatic endothelial cells; tumor immune evasion.

Figure 1

Photomicrographs comparing a heavy lymphocytic infiltrate in a basal phenotype breast carcinoma (A), with a sparse infiltrate in a different basal phenotype breast carcinoma (B) (H&E, original magnification 200×). A similar contrast is seen between a marked CD8⁺ T cell infiltrate in a mismatch repair-deficient colon cancer (C), and the sparse infiltrate in a mismatch repair proficient colon cancer (D). CD8⁺ T cells are seen both within the tumor epithelium (closed arrowhead) and in the tumor stroma (open arrowhead) (CD8 immunohistochemical stain, original magnification 200×).

Figure 2

Molecular mechanisms contributing to the exclusion of immune cells from the tumor microenvironment. Tumor-derived angiogenic factors can block the usual upregulation of cell adhesion molecules in response to inflammatory mediators (endothelial anergy), increase the expression of ETBR, which blocks the clustering of ICAM-1 required for lymphocyte adhesion, and increase expression of cell surface receptors, which selectively decrease CTL extravasation while increasing T_reg extravasation. bFGF, basic fibroblast growth factor; CLEVER-1, common lymphatic endothelial and vascular endothelial receptor-1; CTL, cytotoxic T lymphocyte; EGFL7, epidermal growth factor-like domain 7; ETBR, endothelin B receptor; FasL, Fas ligand; ICAM-1, intercellular adhesion molecule-1; IFNγ, interferon-gamma; IL-1, interleukin-1; TNFα, tumor necrosis factor-α; T_reg, regulatory T cell; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor.

Figure 3

Hypoxia contributes to the recruitment of suppressive immune cells, restricts the maturation and migration of dendritic cells, reduces proliferation and differentiation of effector CTLs, and leads to the upregulation of immune checkpoint molecules such as PD-L1. These effects are mediated through gene regulation by hypoxia-inducible factors and secreted factors such as VEGF-A. CTL, cytotoxic T lymphocyte; DC, dendritic cell; HIF, hypoxia-inducible factor; IL-10, interleukin-10; MDSC, myeloid-derived suppressor cell; T_reg, regulatory T cell; VEGF-A, vascular endothelial growth factor-A.

Figure 4

Lymphatic endothelial cells may contribute to the development of tolerance to tumor antigens by antigen presentation to CD8⁺ T cells in the absence of costimulatory molecules such as CD80/CD86, or in the presence of co-inhibitory molecules such as PD-L1 and LAG3. Peripheral tissue antigens or tumor antigens may be transferred from LECs to dendritic cells, which present these antigens to CD4⁺ T cells in the absence of costimulatory molecules, thereby inducing anergy. Stimulation of LECs by VEGF-C and inflammatory cytokines TNFα and IFNγ can reduce CD86 expression on dendritic cells and produce IDO, which depletes tryptophan from the microenvironment, thereby preventing the activation of T cells. DC, dendritic cell; IDO, indoleamine 2,3-dioxygenase; IFNγ, interferon-gamma; LEC, lymphatic endothelial cell; PTA, peripheral tissue antigen; TNFα, tumor necrosis factor-alpha; VEGF-C, vascular endothelial growth factor-C.