Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors

TLDR

T cell localization and migration are essential for antitumor immune surveillance, yet the mechanisms that drive their preferential accumulation in tumor stroma versus tumor islets remain unclear. The study aims to elucidate how the collagen network is generated, with the goal of informing new therapeutic strategies. Using immunostaining and real‑time imaging of viable human lung tumor slices, the authors demonstrated that stromal extracellular‑matrix density and orientation govern T‑cell migration. T cells migrate actively in loose fibronectin/collagen regions via chemokines, poorly in dense matrix, and are steered by aligned perivascular and tumor‑adjacent fibers away from tumor islets; collagenase‑mediated matrix reduction increases their contact with cancer cells, underscoring the ECM’s role in controlling T‑cell positioning and antitumor immunity.

Abstract

Appropriate localization and migration of T cells is a prerequisite for antitumor immune surveillance. Studies using fixed tumor samples from human patients have shown that T cells accumulate more efficiently in the stroma than in tumor islets, but the mechanisms by which this occurs are unknown. By combining immunostaining and real-time imaging in viable slices of human lung tumors, we revealed that the density and the orientation of the stromal extracellular matrix likely play key roles in controlling the migration of T cells. Active T cell motility, dependent on chemokines but not on β1 or β2 integrins, was observed in loose fibronectin and collagen regions, whereas T cells migrated poorly in dense matrix areas. Aligned fibers in perivascular regions and around tumor epithelial cell regions dictated the migratory trajectory of T cells and restricted them from entering tumor islets. Consistently, matrix reduction with collagenase increased the ability of T cells to contact cancer cells. Thus, the stromal extracellular matrix influences antitumor immunity by controlling the positioning and migration of T cells. Understanding the mechanisms by which this collagen network is generated has the potential to aid in the development of new therapeutics.