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

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.

Glycodelin: A New Biomarker with Immunomodulatory Functions in Non–Small Cell Lung Cancer

“…Both proteins are involved in the regulation of the ECM. In this regard, the dense matrix areas around lung tumors have been shown to strongly reduce T-cell migration (7). Increasing glycodelin concentrations have been linked to deregulated PLAU and MMP9 activity and inhibition of trophoblast invasiveness (11).…”

“…The tumor microenvironment is strongly defined by extracellular matrix (ECM) reorganization and chemokine secretion of tumor cells that leads to a barrier for lymphocytes (7). Infiltration of NSCLCs with lymphocytes is associated with better disease-free survival (8).…”

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

“…In addition, this stringent means for escape from immune surveillance has been noted in other cancers, including the murine B16 melanoma model (27) and human colorectal (28), ovarian (29), and lung cancers (ref. 30; Table 1), raising the possibility of a shared mechanism for the resistance of these three human cancers to anti-PD-1/ anti-PD-L1 (3,4). The mechanism of exclusion in the murine PDA model has been shown to involve CXCL12.…”

Differential Associations of MMP-2 and MMP-14 with Stromal Amounts and T lymphocyte Presence in Ovarian Cancer

“…It seems logical to assume that the degrading action of MMP's on the ECM would facilitate T-lymphocyte infiltration of the tumor stroma followed by infiltration of the tumor mass, but clearly other actions of MMP-14 on signaling pathways are more important. It is possible that chemotactic signals in the micro-environment of the tumor could be more important than the arrangement of the collagen fibers [29,33]. The negative association of MMP-14 on T-lymphocyte influx is in accordance with the negative effect of MMP-14 expression and survival [16].…”

“…When treated with collagenases, T-lymphocyte movement towards the tumor increases. This is in favor of the concept of partial degradation and thus widening of the collagen network for increased T-cell migration [29]. More T-lymphocyte infiltration, especially CD3+CD8+ lymphocytes will result in a better prognosis for the patients [25].…”