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

Author

Listed:
  • Marina T. Broz

    (Cedars-Sinai Medical Center)

  • Emily Y. Ko

    (Cedars-Sinai Medical Center)

  • Kristin Ishaya

    (Cedars-Sinai Medical Center)

  • Jinfen Xiao

    (Cedars-Sinai Medical Center)

  • Marco Simone

    (Cedars-Sinai Medical Center)

  • Xen Ping Hoi

    (Cedars-Sinai Medical Center)

  • Roberta Piras

    (Cedars-Sinai Medical Center)

  • Basia Gala

    (Cedars-Sinai Medical Center)

  • Fernando H. G. Tessaro

    (Cedars-Sinai Medical Center)

  • Anja Karlstaedt

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    University of California)

  • Sandra Orsulic

    (University of California
    University of California)

  • Amanda W. Lund

    (NYU Grossman School of Medicine)

  • Keith Syson Chan

    (Houston Methodist Research Institute)

  • Jlenia Guarnerio

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    University of California
    Cedars-Sinai Medical Center)

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.

Suggested Citation

  • Marina T. Broz & Emily Y. Ko & Kristin Ishaya & Jinfen Xiao & Marco Simone & Xen Ping Hoi & Roberta Piras & Basia Gala & Fernando H. G. Tessaro & Anja Karlstaedt & Sandra Orsulic & Amanda W. Lund & Ke, 2024. "Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46504-4
    DOI: 10.1038/s41467-024-46504-4
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