Soft-tissue sarcomas (STS) are mesenchymal tumors having remarkably diverse histological features. Genomic studies reported that STS have low frequencies of genetic mutation, but often harboring copy number variations (CNVs). For STS, CNVs frequently happen in essential tumor suppressor genes and oncogenic transcriptional genes, neither of which are easily “druggable” targets. Moreover, in concordance with low tumor mutation burden rate, STS show low immunogenicity with less cytotoxic TIL in the TME and is unfortunately linked to a lower responsive rate to PD1/PD-L1 ICB. Using a syngeneic mouse UPS model, we previously found that tumor-associated macrophages (TAM) in the TME are promoting the growth of sarcoma. We further identified specific tumor microenvironmental elements contributing to the pro-tumorigenicity of TAMs, which represent a promising novel clinical target for myeloid-related intervention. Therefore, we hypothesize that exploration of TME is beneficial to identify clinically promising targets for STS. To study the TME in STS, we performed bulk RNA-seq and scRNA-seq on human sarcoma samples which covered different histological subtypes of STS and compare them to normal samples. Our results show that, unlike carcinomas originating from epithelial cells, extracellular matrix (ECM)-related genes are highly upregulated in both cancer-associated fibroblast (CAF) and sarcoma tumor cells. Further analysis show that upregulation of these ECM genes is associated with a worse survival outcome in sarcoma patients. In order to further explore the STS and TME orchestra, we established several syngeneic mouse models according to the genetic aberrations reported in TCGA data. We are currently characterizing these syngeneic mouse models to find out whether they recapitulate human STS samples. Our goal is to utilize these mouse models to study the relationship of ECM-related genes in both CAF and tumor cells, find out the effect of upregulated ECM-related genes on the immune compartment in TME and search for potential therapeutic interventions. Citation Format: Jin-Fen Xiao, Marina Broz, Roberta Piras, Kristin Ishaya, Emily Ko, Jlenia Guarnerio. Profiling tumor microenvironment for therapeutic intervention to soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1364.
Trafficking of T lymphocytes from the lymph nodes to the tumor microenvironment is a critical process of the tumor immunity cycle to elicit cytotoxic anti-tumor responses driven by CD8+ T cells. However, some tumors termed “immune excluded” recruit lymphocytes to the tumor site, but the lymphocytes are unable to penetrate the tumor parenchyma and localize primarily in the peritumoral region. In soft tissue sarcoma patients, most tumors are poorly infiltrated by T cells, which is associated with a poor response to immunotherapies. It has been described that cancer associated fibroblasts (CAFs) are enriched in immune excluded tumors and may directly block the migration of T cells via the production of dense extracellular matrix or by forging an immunosuppressive niche. We generated two models of undifferentiated pleomorphic sarcoma (UPS) that recapitulate the “immune excluded” and “inflamed” microenvironments observed in sarcoma patients. These syngeneic models rely on p53KO mesenchymal stem cells overexpressing either Ccne1 or Vgll3, which are frequently amplified in UPS patients. These models differ in their overall proportion of infiltrating TILs, and specifically T cells, making them ideal for comparative studies to investigate the mechanisms driving T cell exclusion in the TME. Using single-cell RNA-sequencing, we identified a population of CAFs expressing Nt5e, encoding CD73, which are spatially enriched in the peritumoral region of immune excluded Ccne1 tumors and closely associate with CD8+ T cells located at the tumor margin. Using transwell invasion assays, we show that CD73+ CAFs but not CD73- CAFs are able to block the migration of activated T cells towards tumor cells, even in the presence of CXCL10. Further, we show that Nt5e CAFs are enriched for signatures of glucose metabolism, and hypoxia, thus we hypothesized that CD73+ CAFs may block the migration of T cells into tumors by forging a nutrient poor metabolic barrier around the tumor. To test this, we treated Ccne1 tumors with BAY-876, a GLUT1 inhibitor and observed a significant accumulation of infiltrating CD8+ T cells compared to controls. GLUT1 treated CAFs expressed significantly less Nt5e, indicating that CD73 may play a role in the maintenance of glucose metabolism in CAFs. Furthermore, blockade of CD73 in CD73+ CAFs decreases the expression of the glucose transporter, Glut1. All together, these data suggest that CD73 may serve as a marker of glucose dependent CAFs that alter the metabolic niche to block T cell infiltration into tumors. Citation Format: Marina Broz, Emily Ko, Jinfen Xiao, Marco DeSimone, Roberta Piras, Kristin Ishaya, Xen Ping Hoi, Jlenia Guarnerio. Glucose dependent CD73+ CAFs enforce a tumor metabolic barrier that promotes T cell exclusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1255.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.