Abstract A121: Single-cell transcriptomic analyses reveal heterogeneity of vascular endothelial cells in cancer models

Abstract

The immune system has demonstrated promising potential as a therapeutic target in the treatment of certain cancer types, yet in many tumors the efficacy of immunotherapies is still extremely poor. One major obstacle is the limited access of immune cells to the tumor tissue. The tumor vasculature plays critical roles in regulating the recruitment of anti-tumor immune cells and the delivery of immunotherapies to the tumor sites. These immune processes require functional specialization of endothelial cells (ECs). However, there is a major gap in our understanding of the diversity, molecular specialization, and developmental relationships of tumor-associated EC subsets. To understand the heterogeneity of tumor-associated endothelium, we performed single-cell RNA sequencing (scRNAseq) analyses on ECs isolated from mouse cancer models. scRNAseq identified several subsets of endothelium in the tumor tissue, including ECs that compose the artery, capillary, and post-capillary venules. Interestingly, within the capillary endothelial compartment, we identified an EC subset that resembles tip cells in sprouting angiogenesis and demonstrates molecular signature of stem or progenitor cells. These putative progenitor cells are dramatically expanded in tumors compared to normal tissues, and comprise both quiescent and proliferative populations. The quiescent ECs express high levels of genes coding for antiapoptotic proteins, extracellular matrix molecules, immune checkpoint molecules, monocyte/macrophage recruiting cytokines, and stem cell signaling components, such as Notch4. On the other hand, the proliferative tip-like ECs express genes coding for cyclins and cyclin-dependent kinases, DNA damage repair molecules, necroptosis machinery, and epigenetic regulators. Taken together, these data define the heterogeneity of tumor-associated endothelial cells, and reveal a putative progenitor population that gives rise to the tumor vasculature and could be targeted to improve the efficacy of immunotherapies. Citation Format: Yu Zhu, Nicole Salazar, Kevin Brulois, Eugene Butcher. Single-cell transcriptomic analyses reveal heterogeneity of vascular endothelial cells in cancer models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A121.