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

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, Keith Syson Chan and Jlenia Guarnerio ()
Additional contact information
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
Sandra Orsulic: University of California
Amanda W. Lund: NYU Grossman School of Medicine
Keith Syson Chan: Houston Methodist Research Institute
Jlenia Guarnerio: Cedars-Sinai Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46504-4

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