T-cell tolerance in cancer

Abstract

T cells are the master regulators of adaptive immune responses and maintenance of their tolerance is critical to prevent autoimmunity. However, in the case of carcinogenesis, the tumor microenvironment aids T-cell tolerance, which contributes to uncontrolled tumor growth. Recently, there has been significant progress in understanding the intrinsic extracellular (positive and negative costimulatory molecules on APCs) and intracellular mechanisms (E3 ubiquitin ligases, transcriptional and epigenetic repressors), as well as extrinsic mechanisms (Tregs and tolerogenic dendritic cells) that are required for the implementation and maintenance of T-cell tolerance. Ultimately, understanding and manipulating T-cell tolerance will help to break the tolerance state in cancer.

Figure 1. The mechanisms of tumor immune evasion

Under the pressure of the immune system, tumor cell variants develop one or multiple mechanisms to escape attack by the immune system. On the tumor cell level, tumor cells may downregulate antigen presentation to impair recognition by T cells. Tumor cells may also change their expression of apoptotic or prosurvival molecules to avoid the cytotoxic effects from immune cells, and tumor cells secrete immunosuppressive factors and express inhibitory costimulatory molecules to directly inhibit effector T-cell activation. In addition to these intrinsic mechanisms, tumor cells create an immunosuppressive microenvironment by secreting many different suppressive factors, which recruit or promote the differentiation of suppressive immune cells, such as TAMs, MDSCs, Tregs and iDCs. These cells inhibit effector T-cell activation through various different mechanisms. GITR: Glucocorticoid-induced TNF receptor; iDC: Immature dendritic cell; IDO: Indoleamine 2,3-dioxygenase; iNOS: Inducible nitric oxide synthase; MDSC: Myeloid-derived suppressor cell; ROS: Reactive oxygen species; TAM: Tumor-associated macrophage.

Figure 2. NFAT-dependent transcriptional regulation in anergic T cells and Tregs

(A) In tolerant T cells, activation of NFAT alone induces the expression of E3 ubiquitin ligases (Cbl-b, Itch and GRAIL) and transcriptional repressors (Ikaros, Egr2 and 3, CREM, Blimp1, Tob and Smads), which inhibit expression of effector cytokines such as IL-2 and IFN-γ. E3 ubiquitin ligases negatively regulate TCR signaling components. Transcriptional repressors either directly bind to the regulatory elements or mediate their effects by recruiting chromatin modifiers such as HDACs, which deacetylate active histones and silence gene expression. (B) In addition to regulating anergy-associated transcription, NFAT, in complex with Smad3, regulates Foxp3 transcription in Tregs. Foxp3 in turn interacts with many silencing complexes (HDAC7, Tip60 and MBD3) and also with transcription factors such as NFAT and other lineage-specific factors (Tbet, IRF4, RORγ, Bcl6 and Stat3, among others) to silence the target genes. HDAC: Histone deacetylase; TCR: T-cell receptor.