ABSTRACT
Unlike several other tumor types, prostate cancer rarely responds to immune checkpoint blockade (ICB). To define tumor cell intrinsic factors that contribute to prostate cancer progression and resistance to ICB, we analyzed prostate cancer epithelial cells from castration-sensitive and -resistant samples using implanted tumors, cell lines, transgenic models and human tissue. We found that castration resulted in increased expression of interleukin-8 (IL-8) and its probable murine homolog Cxcl15 in prostate epithelial cells. We showed that these chemokines drove subsequent intratumoral infiltration of tumor-promoting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was largely abrogated when IL-8 signaling was blocked genetically or pharmacologically. Targeting IL-8 signaling in combination with ICB delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Our findings establish a novel mechanism by which castration mediates IL-8 secretion and subsequent PMN-MDSC infiltration, and highlight blockade of the IL-8/CXCR2 axis as a potential therapeutic intervention.
Subject(s)
Myeloid-Derived Suppressor Cells , Prostatic Neoplasms , Animals , Castration , Humans , Interleukin-8/genetics , Male , Mice , Prostate , Prostatic Neoplasms/geneticsABSTRACT
Vascular diversity among organs has recently become widely recognized. Several studies using mouse and human fetal tissues revealed distinct characteristics of organ-specific vasculature in molecular and functional levels. Thorough understanding of vascular heterogeneities in human adult tissues is significant for developing novel strategies for targeted drug delivery and tissue regeneration. Recent advancements in microfabrication techniques, biomaterials, and differentiation protocols allowed for incorporation of microvasculature into engineered organs. Such vascularized organ models represent physiologically relevant platforms that may offer innovative tools for dissecting the effects of the organ microenvironment on vascular development and expand our present knowledge on organ-specific human vasculature. In this article, we provide an overview of the current structural and molecular evidence on microvascular diversity, bioengineering methods used to recapitulate the microenvironmental cues, and recent vascularized three-dimensional organ models from the perspective of tissue-specific vasculature.
