Non-hematopoietic Control of Peripheral Tissue T Cell Responses: Implications for Solid Tumors

Abstract

In response to pathological challenge, the host generates rapid, protective adaptive immune responses while simultaneously maintaining tolerance to self and limiting immune pathology. Peripheral tissues (e.g., skin, gut, lung) are simultaneously the first site of pathogen-encounter and also the location of effector function, and mounting evidence indicates that tissues act as scaffolds to facilitate initiation, maintenance, and resolution of local responses. Just as both effector and memory T cells must adapt to their new interstitial environment upon infiltration, tissues are also remodeled in the context of acute inflammation and disease. In this review, we present the biochemical and biophysical mechanisms by which non-hematopoietic stromal cells and extracellular matrix molecules collaborate to regulate T cell behavior in peripheral tissue. Finally, we discuss how tissue remodeling in the context of tumor microenvironments impairs T cell accumulation and function contributing to immune escape and tumor progression.

Keywords: T cell; extravasation; fluid flow; immunotherapy; interstitial migration; non-hematopoietic cells; trafficking.

Figure 1

Blood endothelial cells control T cell entry into inflamed tissue. (A) The vascular endothelium limits T cell infiltration at steady-state by low expression of selectins and cell adhesion molecules (CAMs), and stabilized endothelial cell-cell junctions, due in part to tonic nitric oxide (NO) signaling and laminin α5-mediated VE-cadherin stabilization. (B) In response to pathological challenge and inflammatory stimulus (e.g., TNFα, IL-1β, LPS), blood endothelial cells (BECs) become activated and increase expression of selectins, CAMs and chemokines, which promote lymphocyte adhesion and migration to sites permissible for transmigration. In some cases, BECs form a transmigratory cup that provides a perpendicular scaffold to direct T cell transmigration. Inflammatory remodeling of the basement membrane contributes to lymphocyte access through destabilization of VE-cadherin at endothelial junctions and by generating low-density sites permissive to lymphocyte migration.

Figure 2

Interstitial matrices control T cell migration through inflamed tissue. (A) At steady-state T cells exhibit integrin-independent amoeboid-like Lévy walk behavior (dotted line) that facilitates their surveillance of peripheral tissue. (B) During inflammation fibroblast activation alters tissue tension through increased deposition, bundling, and cross-linking of extracellular matrix (ECM) components thereby altering the scaffold across which T cells must migrate. Increased interstitial fluid flows that result from vascular permeability further activate fibroblasts and promote directional fiber alignment. These inflammation-induced ECM changes activate integrin-dependent lymphocyte migration along collagen bundles. Whether T cell migration is dependent upon ECM organization or if rather lymphocytes may activate proteolytic activity to promote tissue invasion remains largely unclear. Facilitating T cell position at the site of challenge are chemokine gradients (e.g., CXCL9/10) that increase lymphocyte velocity (v) thereby improving their Lévy walk search efficiency and permitting accumulation at and around target cells.

Figure 3

Inflamed lymphatic vessels promote lymphocyte exit from tissue. (A) Steady state lymphatic endothelial cells (LEC) form loose button-like junctions in lymphatic capillaries, and constitutively transport interstitial fluid from peripheral non-lymphoid tissue to draining lymph nodes. Production of homoestatic chemokines, such as CCL21, supports immune surveillance by directing leukocyte homing toward lymphatic vessels and tissue egress. (B) During inflammation, lymphatic vessels respond to both biochemical and biophysical stimuli to adapt their function within the tissue. Lymphatic vessels are activated by inflammatory cytokines and elevated interstitial fluid flow resulting in increased expression of selectins, cell adhesion molecules (CAMs) and context-dependent chemokine secretion that together promotes lymphocyte egress from inflamed tissues. LECs remodel their junctions, going from loose, button-like junctions to tight, zipper-like junctions, which is associated with decreased fluid transport from inflamed tissues and subsequent increased interstitial fluid pressures.

Figure 4

Non-hematopoietic cell contribution to tumor immune landscapes. The geographic distribution of T cells within intratumoral and peritumoral regions is both predictive of overall survival and response to immunotherapy. Patients that fail to respond to immunotherapy often exhibit three patterns of T cell infiltrate that are governed by an array of mechanisms including contributions from tumor cells and infiltrating hematopoietic cells. Non-hematopoetic cells, however, additionally contribute to the infiltration, retention, and function of T lymphocytes in tumor microenvironments. (1) Non-functional infiltrate: possessing an intratumoral but seemingly ineffective infiltrate. Antigen-independent recruitment of both effector and memory T cells subsets by vascular endothelium generates a diverse repertoire of T cells both relevant and irrelevant for tumor killing. Upon tissue entry, non-hematopoietic cells further exert multiple mechanisms of immune suppression, including expression of immune checkpoints such as PD-L1 and FasL that limit local T cell function. (2) Excluded infiltrate: possessing a T cell infiltrate that is restricted to the tumor periphery. Establishment of matrix barriers, collapsed intratumoral vessels, poor expression of adhesion molecules, and collaborating chemoattractant and chemorepellant gradients likely all contribute to the exclusion of T cells at the periphery of tumor nests such that inhibition of these features may improve infiltration. (3) Immunological desert: Completely lacking a T cell infiltrate in both tumor nests and stroma. Impaired lymphatic transport may result in poor antigen delivery to lymph nodes and thus poor priming. However, even in the presence of an activated systemic T cell pool, non-functional vessels driven by the angiogenic and desmoplastic tumor microenvironment may prevent local infiltration leading to lesion-specific differences in immune infiltrates.