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

[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.
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 [...]