Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment

J Clin Invest. 2024 Apr 23;134(11):e167826. doi: 10.1172/JCI167826.


CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.

Keywords: Cancer immunotherapy; Extracellular matrix; Oncology; Skeletal muscle.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • CD8-Positive T-Lymphocytes* / immunology
  • CD8-Positive T-Lymphocytes* / pathology
  • Collagen Type I / genetics
  • Collagen Type I / immunology
  • Collagen Type I / metabolism
  • Collagen Type VI / genetics
  • Collagen Type VI / immunology
  • Collagen Type VI / metabolism
  • Extracellular Matrix* / immunology
  • Extracellular Matrix* / metabolism
  • Extracellular Matrix* / pathology
  • Humans
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism
  • Oncogenes
  • Sarcoma* / genetics
  • Sarcoma* / immunology
  • Sarcoma* / metabolism
  • Sarcoma* / pathology
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Tumor Microenvironment* / immunology
  • YAP-Signaling Proteins* / genetics
  • YAP-Signaling Proteins* / immunology


  • YAP-Signaling Proteins
  • Collagen Type VI
  • YAP1 protein, human
  • Yap1 protein, mouse
  • Adaptor Proteins, Signal Transducing
  • Transcription Factors
  • Neoplasm Proteins
  • Collagen Type I