Abstract
The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1β, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1β and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients.
Highlights
Virchow first identified a link between inflammation and cancer in the late 1800s [1]
We found by linear regression analysis, that increases in vascular area seen with anti-Vascular endothelial growth factor-A (VEGF) therapy correlated with changes in IL-1b and IL-6 (Fig. 7B & C; Table 2), suggesting an alternative pathway for angiogenesis in the presence of anti-VEGF therapy
We provide data that demonstrate the effectiveness of anti-VEGF therapy as a modulator of immune cell infiltration, and intra-tumoral and serum cytokine levels in multiple preclinical models of breast cancer
Summary
Virchow first identified a link between inflammation and cancer in the late 1800s [1]. The concept that chronic inflammation in the tumor microenvironment contributes to tumor progression has been validated in many types of cancer [1,2,3]. It is clear that chronically activated immune cells can promote tumor growth and facilitate tumor survival. Macrophages are typically the main inflammatory component, but a variety of immune cells infiltrate tumors and can participate in tumor promotion [6]. These cells confer a worse prognosis in many types of cancer, including breast cancer [7]
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