Engaging the Immune Response to Normalize the Tumor Microenvironment

Solid tumors exist as heterogeneous populations comprised not only of malignant cells, but various other cell types, including cells that make up the vasculature, that can strongly influence tumorgenicity. Many forms of solid cancers are highly vascularized due to dysregulated angiogenesis. The tumor vasculature is classified by leaky, chaotic blood vessels consisting of several components including vascular endothelial cells and pericytes, as well vascular progenitors, resulting in vascular permeability and high interstitial pressure. As a result, the tumor vasculature limits the access of immune effector cells to the tumor, and may in part be responsible for the modest success observed in many current anti-cancer immunotherapies. Current first-line therapeutics in the advanced stage disease setting include anti-angiogenic small molecule drugs that have yielded high objective clinical response rates, however these responses tend to be transient in nature, with most patients becoming drug-refractory. Anti-tumor vasculature vaccines may promote the reconditioning of the tumor microenvironment by coordinately promoting a pro-inflammatory environment and the specific immune targeting of tumor-associated stromal cell populations that contribute to vasculature destabilization. Implementing a vaccine with these therapeutic effects is a promising treatment option that may extend disease-free intervals and overall patient survival. I show that vaccines specifically targeting tumor vasculature populations can “normalize” the tumor microenvironment, as shown by upregulation of proinflammatory molecules within the tumor as well as vascular remodeling promoting enhanced recruitment of CD8+ T cells, resulting in superior anti-tumor efficacy