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

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• CD8+ T cell dysfunction limits antitumor immunity in solid tumors.
• The tumor microenvironment's extracellular matrix (ECM) influences T cell function, but specific molecular impacts are unclear.
• Dysregulated ECM deposition in tumors lacks well-defined upstream regulators.

Purpose of the Study:

• To investigate how ECM composition affects CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS).
• To identify upstream regulators of ECM deposition in the UPS tumor microenvironment (TME).

Main Methods:

• Utilized an autochthonous murine model of UPS.
• Analyzed data from multiple human patient cohorts.
• Investigated the role of YAP1, collagen VI (COLVI), and collagen I (COLI) in the UPS TME.

Main Results:

• YAP1 promotes COLVI deposition in the UPS TME.
• COLVI inhibits CD8+ T cell function by remodeling collagen and impairing T cell autophagic flux, promoting immune evasion.
• COLI counteracted COLVI's effects, enhancing CD8+ T cell function and acting as a tumor suppressor.

Conclusions:

• Sarcoma CD8+ T cell responses are critically dependent on oncogene-driven ECM composition and remodeling.
• YAP1-mediated COLVI deposition is a key mechanism of immune evasion in UPS.
• Targeting ECM composition, specifically the balance of COLVI and COLI, may represent a therapeutic strategy to enhance antitumor immunity.