VEGF and pleiotrophin modulate the immune profile of breast cancer

Abstract

Angiogenesis, the sprouting of the existing vascular network to form new vessels, is required for the growth of solid tumors. For this reason, the primary stimulant of angiogenesis, vascular endothelial growth factor-A (VEGF), is an attractive target for tumor therapy. In fact, there are currently numerous anti-VEGF therapies in clinical development for the treatment of various cancers, including breast cancer. VEGF signals through two primary VEGF receptors, VEGFR1 and VEGFR2. VEGFR2 is the primary angiogenic receptor, and VEGFR1 has been implicated in macrophage chemotaxis and tumor cell survival and invasion. It has only been appreciated recently that the VEGFRs are expressed not only on endothelial cells and tumor cells but also on many host immune cells. Therefore, to better understand the effects of anti-VEGF therapy it is important to consider the effects of VEGF on all cells in the tumor microenvironment, including immune cells. Bevacizumab (Avastin®, Genetech), which binds VEGF and inhibits interaction with VEGFR1 and VEGFR2, was approved for the treatment of metastatic HER2/NEU-negative breast cancer in 2008, however, the majority of human mammary tumors are either innately resistant or will acquire resistance to anti-VEGF therapy. This suggests that these tumors activate alternate angiogenesis pathways. Pleiotrophin (PTN) is an important angiogenic cytokine in breast cancer and is expressed at high levels in approximately 60% of human breast tumors. PTN functions as an angiogenic factor and promotes remodeling of the tumor microenvironment as well as epithelial-mesenchymal transition (EMT). In addition, PTN can have profound effects on macrophage phenotype. The present review focuses on the functions of VEGF and PTN on immune cell infiltration and function in breast cancer. Furthermore, we will discuss how anti-VEGF therapy modulates the immune cell profile.

Figure 1

Macrophage infiltration correlates with the accumulation of CD25⁺ FoxP3⁺ regulatory T-cells in two pre-clinical models of breast cancer following anti-VEGF therapy. Mice in each experiment received therapy with either control antibody (C44), mouse-chimeric r84 (inhibits the VEGF: VEGFR2 interaction), sunitinib (inhibits VEGFR1, VEGFR2 PDGFRβ, c-kit), or GU81 (inhibits VEGFR1 and VEGFR2). (A, B) By linear regression analysis, changes intra-tumoral T_reg number following anti-VEGF therapy positively correlate with CD68⁺ macrophage levels after four weeks of therapy in the 4T1 syngeneic (A) and MMTV-PyMT transgenic breast cancer models (B). Each dot represents the mean for CD68⁺ area and the number of T_regs in each treatment group. (C, D) By linear regression analysis, changes in intra-tumor T_reg number positively correlate with the number of CD11b+ Gr1+ MDSCs following four weeks of therapy in the 4T1 syngenic (C) but not the MMTV-PyMT transgenic (D) breast cancer model. Each dot represents the mean for the number of MDSCs and T_regs in each treatment group.