Data from Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment

Abstract

<div>Abstract<p>Stromal cells are physiologically essential components of the tumor microenvironment (TME) that mediates tumor development and therapeutic resistance. Development of a logical and unified system for stromal cell type identification and characterization of corresponding functional properties could help design antitumor strategies that target stromal cells. Here, we performed a pan-cancer analysis of 214,972 nonimmune stromal cells using single-cell RNA sequencing from 258 patients across 16 cancer types and analyzed spatial transcriptomics from 16 patients across seven cancer types, including six patients receiving anti–PD-1 treatment. This analysis uncovered distinct features of 39 stromal subsets across cancer types, including various functional modules, spatial locations, and clinical and therapeutic relevance. Tumor-associated <i>PGF</i><sup>+</sup> endothelial tip cells with elevated epithelial–mesenchymal transition features were enriched in immune-depleted TME and associated with poor prognosis. Fibrogenic and vascular pericytes (PC) derived from <i>FABP4</i><sup>+</sup> progenitors were two distinct tumor-associated PC subpopulations that strongly interacted with <i>PGF</i><sup>+</sup> tips, resulting in excess extracellular matrix (ECM) abundance and dysfunctional vasculature. Importantly, ECM-related cancer-associated fibroblasts enriched at the tumor boundary acted as a barrier to exclude immune cells, interacted with malignant cells to promote tumor progression, and regulated exhausted <i>CD8</i><sup>+</sup> T cells via immune checkpoint ligand–receptors (e.g., LGALS9/TIM-3) to promote immune escape. In addition, an interactive web-based tool (<a href="http://www.scpanstroma.yelab.site/" target="_blank">http://www.scpanstroma.yelab.site/</a>) was developed for accessing, visualizing, and analyzing stromal data. Taken together, this study provides a systematic view of the highly heterogeneous stromal populations across cancer types and suggests future avenues for designing therapies to overcome the tumor-promoting functions of stromal cells.</p>Significance:<p>Comprehensive characterization of tumor-associated nonimmune stromal cells provides a robust resource for dissecting tumor microenvironment complexity and guiding stroma-targeted therapy development across multiple human cancer types.</p></div>