Positive and negative influence of the matrix architecture on antitumor immune surveillance

Abstract

The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells.

Fig. 1

Spatial organization of tumor cells, T cells and ECM components in human lung and ovarian carcinomas. a In a human lung tumor, tumor cells (brown, stained for cytokeratin) form well-delineated tumor islets surrounded by a stroma (blue). b In a human lung tumor, T cells (brown, stained for CD3) are preferentially distributed within the tumor stroma and very rarely in contact with tumor cells. Dotted white lines denote tumor islets. c In a human lung tumor, thick and linear fibronectin fibers (brown, stained for fibronectin) surround tumor islets denoted by dotted white lines. d In a human ovarian tumor, tumor cells (red, stained for EpCAM) are surrounded by straight and parallel collagen fibers (green) detected by SHG on a two-photon microscope. Bar 100 μm

Fig. 2

Characteristics of reticular fiber and fibrotic networks. The reticular fiber network of secondary and tertiary lymphoid organ is composed of light and spaced fibers made by FRC. This network provides a guidance path for T cells that migrate rapidly onto FRC coated with chemokines (left). Fibrotic networks are characterized by dense and parallel matrix fibers generated by activated fibroblasts. Fibrotic networks are unfavorable migration zone for T cells which hardly move between dense fibers (right). Features of both networks are described in Table 1

Fig. 3

Distribution of T cells in relation to fibronectin fibers and tumor cells in a human lung tumor. Tumor islets (blue, stained for EpCAM) are surrounded by dense and tight fibronectin fibers (red, stained for fibronectin). T cells (green, stained for CD3) are sparse in regions immediately adjacent to the tumor mass but concentrated in light matrix fiber areas. Bar 100 μm

Fig. 4

Promising targets for rendering the tumor stroma more permissive to T cells. Strategies to decrease the dense ECM network include the inhibition of collagen cross-linking enzymes such as LOX, the inhibition of fibroblast activation and the degradation of pre-existing matrix fibers. Strategies to promote the development of reticular fiber networks include the targeting of lymphotoxin β receptor