Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors
Hélène Salmon, Katarzyna Franciszkiewicz, Diane Damotte, Marie-Caroline Dieu-Nosjean, Pierre Validire, Alain Trautmann, Fathia Mami-Chouaib, Emmanuel Donnadieu
Hélène Salmon, Katarzyna Franciszkiewicz, Diane Damotte, Marie-Caroline Dieu-Nosjean, Pierre Validire, Alain Trautmann, Fathia Mami-Chouaib, Emmanuel Donnadieu
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Research Article Immunology

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.

Authors

Hélène Salmon, Katarzyna Franciszkiewicz, Diane Damotte, Marie-Caroline Dieu-Nosjean, Pierre Validire, Alain Trautmann, Fathia Mami-Chouaib, Emmanuel Donnadieu

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Figure 3

T cell migration within human lung tumor slices is partially inhibited by PTX.

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T cell migration within human lung tumor slices is partially inhibited b...
(A) Tracks of individual suB- (green) or PTX-treated (red) T cells in a human lung tumor slice during a 20-minute recording with a widefield microscope. T cells were incubated for 2 hours with 100 ng/ml suB or PTX, labeled with CMFDA and Hoechst, respectively, and overlaid on a tumor slice. Stroma was identified by staining for fibronectin (not shown). (B) Motility coefficient of suB- and PTX-treated T cells within the whole stroma and within hot spots, in which lymphocyte motility was favored (see D). Values are mean and SD from experiments performed on tumor slices from 5 different lung cancer patients. At least 100 cells were analyzed per experiment. (C) Tracks of individual suB- (green) and PTX-treated (red) T cells measured in a microscopic field of a human lung tumor slice during a 20-minute recording. 7 200-μm × 200-μm adjacent stromal regions (R1–R7) are indicated. (D) Motility coefficient of suB- and PTX-treated T cells analyzed within the 7 adjacent stromal regions in C. Dashed lines denote the 10-μm2/min threshold for hot spots. **P < 0.01. Scale bars: 50 μm (A); 100 μm (C).