Collagen type I promotes pancreatic tumor growth and limits immune cell infiltration

Abstract Solid tumors are often characterized by a dense extracellular matrix (ECM) that contributes to increased tissue stiffness. Collagen type I is the main component of the ECM and its abundance in tumors is frequently associated with poor prognosis. In vitro studies suggest that a high collagen density promotes tumor invasion and modulates immune responses. However, recent in vivo findings have questioned the pro-tumorigenic role of collagen type I. In this study, we investigate the role of collagen for pancreatic tumor growth and immune cell infiltration using conditional collagen type I knockout mice and transgenic collagenase-resistant mice. Preventing collagen type I significantly reduces intratumoral collagen content and tumor growth. This reduction is accompanied increased infiltration of natural killer (NK) cells, a higher CD8/CD4 T cell ratio, and decreased numbers of monocytic myeloid-derived suppressor cells (MDSCs). Conversely, collagenase-resistant mice develop collagen-dense tumors and display enhanced tumor growth. These mice also generally exhibit opposing effects on cell infiltration, including a lower CD8/CD4 ratio and increased MDSC abundance. These findings are further supported by analyses of publicly available human cancer datasets, which confirm an association between collagen type I levels and immune cell infiltration. Overall, our results demonstrate a pronounced pro-tumorigenic role of collagen type I in pancreatic cancer, which is associated with modulation of the tumor immune microenvironment. This study highlights the importance of extracellular matrix components as key regulators of tumor progression and anti-tumor immunity.