2. Academic Validation
  3. Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas

Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas

  • Nat Commun. 2024 Mar 20;15(1):2498. doi: 10.1038/s41467-024-46504-4.
Marina T Broz 1,  Emily Y Ko 2,  Kristin Ishaya 2,  Jinfen Xiao 2,  Marco De Simone 2,  Xen Ping Hoi 1,  Roberta Piras 1,  Basia Gala 1,  Fernando H G Tessaro 2,  Anja Karlstaedt 1 3 4,  Sandra Orsulic 4 5,  Amanda W Lund 6,  Keith Syson Chan 7,  Jlenia Guarnerio 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 2 Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 3 Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 4 David Geffen Medical School, Department of Medicine, University of California, Los Angeles, CA, USA.
  • 5 Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • 6 Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA.
  • 7 Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
  • 8 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
  • 9 Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
  • 10 David Geffen Medical School, Department of Medicine, University of California, Los Angeles, CA, USA. [email protected].
  • 11 Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
PMID: 38509063 DOI: 10.1038/s41467-024-46504-4
Abstract

T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we characterize the STS microenvironment using murine models (in female mice) with distinct immune composition by scRNA-seq, and identify a subset of CAFs we termed glycolytic cancer-associated fibroblasts (glyCAF). GlyCAF rely on GLUT1-dependent expression of CXCL16 to impede cytotoxic T-cell infiltration into the tumor parenchyma. Targeting glycolysis decreases T-cell restrictive glyCAF accumulation at the tumor margin, thereby enhancing T-cell infiltration and augmenting the efficacy of chemotherapy. These findings highlight avenues for combinatorial therapeutic interventions in sarcomas and possibly other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-100017
    98.46%, GLUT1 Inhibitor