Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment

Abstract

Immunotherapeutic drugs including immune checkpoint blockade antibodies have been approved to treat patients in many types of cancers. However, some patients have little or no reaction to the immunotherapy drugs. The mechanisms underlying resistance to tumor immunotherapy are complicated and involve multiple aspects, including tumor-intrinsic factors, formation of immunosuppressive microenvironment, and alteration of tumor and stromal cell metabolism in the tumor microenvironment. T cell is critical and participates in every aspect of antitumor response, and T cell dysfunction is a severe barrier for effective immunotherapy for cancer. Emerging evidence indicates that extracellular vesicles (EVs) secreted by tumor is one of the major factors that can induce T cell dysfunction. Tumor-derived EVs are widely distributed in serum, tissues, and the tumor microenvironment of patients with cancer, which serve as important communication vehicles for cancer cells. In addition, tumor-derived EVs can carry a variety of immune suppressive signals driving T cell dysfunction for tumor immunity. In this review, we explore the potential mechanisms employed by tumor-derived EVs to control T cell development and effector function within the tumor microenvironment. Especially, we focus on current understanding of how tumor-derived EVs molecularly and metabolically reprogram T cell fates and functions for tumor immunity. In addition, we discuss potential translations of targeting tumor-derived EVs to reconstitute suppressive tumor microenvironment or to develop antigen-based vaccines and drug delivery systems for cancer immunotherapy.

Keywords: adaptive immunity; immune evation; immune tolerance; immunotherapy; tumor microenvironment.

Figure 1

Mechanisms for tumor-derived EV-mediated suppression on T cells. Tumors are surrounded by different types of stromal cells within a microenvironment that the tumor closely interacts with. Within this microenvironment, there are blood vessels, fibroblasts, and T lymphocytes, as well as environmental secreted factors including exosomes derived from the tumor. These EVs further induce dysfunction of T cells in the suppressive tumor microenvironment mainly through several ways, including (1) inhibition of T cell proliferation, effector immune responses and cytotoxicity through EV components TGF-β, miRNA, arginase, PD-L1, Gal-1, CD73, CD39, SALL4 and PGE2; (2) suppression of T helper cell differentiation through EV components miRNA, TGF-β, and 14-3-3ζ; (3) expansion and recruitment of Treg cells via EV cargoes CD39, C73, PD-L1, CCL20, TGF-β, 14-3-3ζ and miRNA; (4) induction of T cell apoptosis and/or exhaustion through FasL, TRAIL, Gal-9, 14-3-3ζ, SALL4, circRNA and miRNA; (5) reprogramming of T cell metabolism through EV cargos PGE2, CD39, CD73 and arginase to increase cellular adenosine and cAMP levels, or decrease amino acid; and (6) indirect suppression of T cell function via impairing DC maturation, migration, and antigen presentation through components PD-L1, TGF-β and PGE2. DC function impairment also contributes to MDSC and Treg cells expansion, which further lead to T cell suppression. CCL20, C-C motif chemokine ligand 20; circRNAs, circular RNA; DC, dendritic cell; EV, extracellular vesicle; FasL, Fas ligand; Gal, galectin; MDSC, myeloid-derived suppressor cells; miRNAs, microRNAs; PD-L1, programmed death-ligand 1; PGE2, prostaglandin E2; SALL4, spalt like transcription factor 4; TGF-β, transforming growth factor beta; Treg, regulatory T cell.