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

Abstract

CD8+ T cell dysfunction is a critical barrier to anti-tumor immunity, but molecular mechanisms underlying the regulation of T cell dysfunction in solid tumors are diverse and complex. Extracellular matrix (ECM) composition facilitates solid tumor progression in part by inhibiting T cell migration/infiltration; however, the impact of individual ECM molecules on T cell function in the tumor microenvironment (TME) is virtually unknown. Moreover, upstream regulators of aberrant ECM deposition/organization in solid tumors are poorly defined. Therefore, we investigated the regulation and effects of ECM composition on CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS). This immunologically "hot" soft-tissue sarcoma exhibits durable responses to checkpoint therapy in some human patients, suggesting it may provide insights into strategies for optimizing T cell function and improving immunotherapy efficacy. Using an autochthonous model of UPS and data from multiple human patient cohorts, we discovered a multi-pronged mechanism wherein oncogene-induced remodeling of the TME promotes CD8+ T cell dysfunction, suppresses T cell-mediated cytolysis, and enhances immune evasion. Specifically, we observed that the transcriptional co-activator Yap1, which we previously linked to UPS progression, promotes the aberrant deposition of collagen VI in the UPS TME. In turn, collagen VI induces CD8+ T cell dysfunction by inhibiting T cell autophagic flux and remodeling fibrillar collagen architecture in the TME. Furthermore, collagen type I opposed ColVI in this setting, acting as tumor suppressor. Thus, our findings reveal that CD8+ T cell-mediated anti-tumor immunity in solid cancers is dependent upon oncogene-mediated ECM composition and remodeling in the TME.