Journal Article

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

Ntekoumes, Dimitris, Weber, Kristy, Gonzalez, Michael V., Devalaraja, Samir, Song, Hoogeun, Williams, Erik F., Zabransky, Daniel J., Fuller, Ashley M., Gerecht, Sharon, Hakonarson, Hakon, Pruitt, Hawley C., Liu, Ying, Ciotti, Gabrielle E., Skuli, Nicolas, Pan, Hehai, Katti, Rohan S., Trevino, Jose G., DeVine, Ann, Murazzi, Ileana, Weeraratna, Ashani, Eisinger-Mathason, T.S. Karin, Haldar, Malay, Irizarry-Negron, Valerie M., Fraietta, Joseph A.

2024

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - immunology / Adaptor Proteins, Signal Transducing - metabolism / Animal models / Animals / Antigens / Cancer / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - pathology / Cell adhesion & migration / Cell migration / Collagen / Collagen (type I) / 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 / Extracellular Matrix - immunology / Extracellular Matrix - metabolism / Extracellular Matrix - pathology / Gene expression / Humans / Hypotheses / Immunotherapy / Lymphocytes / Lymphocytes T / Mice / Musculoskeletal system / Neoplasm Proteins - genetics / Neoplasm Proteins - immunology / Neoplasm Proteins - metabolism / Oncogenes / Oncology / Roles / Sarcoma / Sarcoma - genetics / Sarcoma - immunology / Sarcoma - metabolism / Sarcoma - pathology / Solid tumors / T cell receptors / Transcription Factors - genetics / Transcription Factors - immunology / Transcription Factors - metabolism / Tumor microenvironment / Tumor Microenvironment - immunology / Tumor suppressor genes / Tumors / YAP-Signaling Proteins - genetics / YAP-Signaling Proteins - immunology / Yes-associated protein