Inhibiting the Secreted RGDKGE Collagen Peptide Selectively Controls CD8⁺ T-Cell Migration on Denatured Collagen-IV...

The ability of the immune system to control malignant tumors depends in part on the migratory ability of CD8⁺ T cells. Developing in-depth cellular and molecular understanding into how changes in the structural organization of collagen-IV differentially governs site-specific CD8⁺ T-cell migration through restrictive tissue barriers is challenging given the dynamic biomechanical alterations occurring in the basement membranes of tumor blood vessels. Thus, uncovering new mechanisms regulating CD8⁺ T-cell migration through structurally altered or denatured collagen-IV may allow the development of clinically useful strategies to selectively enhance immune cell infiltration of tumors in a context-dependent manner. This work provides evidence that a secreted RGDKGE-containing collagen peptide limits CD8⁺ T-cell migration on denatured forms of collagen-IV, but not on normal triple helical collagen-IV by a unique mechanism. This novel pathway involves the context-dependent regulation of myosin IXB (MYO9B) and Yes-associated protein-1 (YAP) in CD8⁺ T cells, ultimately leading to altered F-actin polarization and selectively reduced migration on denatured collagen-IV that is enriched in basement membranes of tumor vessels. In addition to defining a previously unknown mechanism that contributes to the site-specific control of CD8⁺ T-cell migration, these studies provide a strategy to selectively reverse the inhibitory effects of this endogenously secreted collagen peptide using a function-blocking antibody, resulting in enhanced accumulation of CD8⁺ T cells in tumors growing in vivo.