1. Oncogene-induced matrix reorganization controls [CD8.sup.+] T cell function in the soft-tissue sarcoma microenvironment
- Author
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Fuller, Ashley M., Pruit, Hawley C., Ying, Liu, Irizarry-Negron, Valerie M., Pan, Hehai, Song, Hoogeun, DeVine, Ann, Katti, Rohan S., Devalaraja, Samir, Ciotti, Gabrielle E., Gonzalez, Michael V., Williams, Erik F., Murazzi, Ileana, Ntekoumes, Dimitris, Skuli, Nicolas, Hakonarson, Hakon, Zabransky, Daniel J., Trevino, Jose G., Weeraratna, Ashani, Weber, Kristy, Haldar, Malay, Fraietta, Joseph A., Gerech, Sharon, and Eisinger-Mathason, T.S. Karin
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Control ,Influence ,Physiological aspects ,Models ,Development and progression ,Risk factors ,Health aspects ,Oncogenes -- Physiological aspects -- Influence -- Health aspects ,Sarcoma -- Risk factors -- Development and progression -- Models ,T cells -- Physiological aspects -- Health aspects -- Control - Abstract
Introduction Immunosuppression in the solid tumor microenvironment (TME) impedes T cell-mediated antitumor immunity. Tumors evade host adaptive immune responses by inducing [CD8.sup.+] T cell dysfunction, a hypofunctional state characterized by [...], [CD8.sup.+] 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.sup.+] 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.sup.+] 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.sup.+] T cell function and acting as a tumor suppressor. Thus, [CD8.sup.+] T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.
- Published
- 2024
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