Regulatory effects of IRF4 on immune cells in the tumor microenvironment

Abstract

The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

Keywords: IRF4; T cell exhaustion; immunoregulation; immunosuppressive cells; tumor microenvironment.

Figure 1

Graphical abstract. In contrast to lineage-specific TFs, IRF4 plays an important role in T cell differentiation and function by regulating the expression of corresponding transcription factors (TFs) to control the generation of other lineages, particularly the differentiation and proliferation of effector T cells, promoting anti-tumor immunity. However, persistently high expression of IRF4 and AP1 family members leads to overabundance of IRF4/AP1 complexes to drive T cell exhaustion. In addition, IRF4 plays an important role in the development and function of a series of immunosuppressive cells, such as MDSCs, TAMs, immature DCs, Treg cells and Th2 cells, maintaining immune homeostasis and in parallel establishing an immunosuppressive TME and inhibiting anti-tumor immunity.

Figure 2

Schematic diagram of IRF4 structure. IRF4 consists of three structural domains: a highly conserved N-terminal DNA-binding domain (DBD), a variable C-terminal IRF association domain (IAD) and an intermediate linker domain (ILD). The DBD is characterized by five conserved tryptophans enabling it to form a helix–loop–helix motif that facilitates DNA binding. IAD is a protein–protein interaction domain that mediates the interaction of IRF4 with itself or multiple distinct transcription factors. IAD also contains a C-terminal auto-inhibitory region (AR) which physically interacts with DBD and results in low DNA binding affinity.

Figure 3

Dual regulatory effects of IRF4 on T cell immunity and underlying mechanisms. (A) Antigen stimulation drives and induces the expression of IRF4, which contributes to maintaining the expansion and sustained differentiation of effector CD8+ T cells. However, sustained overexpression of IRF4 due to chronic antigen stimulation drives CD8+ T cell exhaustion. Mechanically, (B) once antigen stimulation, IRF4 is induced and combined with its binding partners to form activating IRF4/AP1 complexes, thus inducing the production of effector cytokines and exerting cytotoxic activity. Once antigen clearance, the expression of IRF4 decreases, followed by an increase in expression of stemness-like gene TCF7 expression, thus producing TCF1+ memory-like T cells; (C) however, persistent overexpression of IRF4 and AP1 family members, such as BATF, BATF3 and JunB, leads to the formation of immunosuppressive IRF4/AP1 complexes, which opens multiple exhaustion-related chromatin regions, promoting the expression of inhibitory receptors and NR4A and TOX family members, which inhibits TCF7 expression and eventually drives CD8+ T cell exhaustion.

Figure 4

The effects of IRF4 on the crosstalk between immunosuppressive cells and T cells in the TME. Tumor cells and multiple soluble chemokines and cytokines recruit and induced various immunosuppressive cells, such as MDSCs, TAMs and DCs to the TME, which further aggravate the TME disorder and promote tumor growth. These myeloid derived immunosuppressive cells can suppress the effector function of CTL and Th1 cells and promote the differentiation of Treg cells and Th2 cells. In addition, tumor-related antigens stimulate the abnormal activation of effector T cells, ultimately, lead to the CD8+ T cell exhaustion, characterized by up-regulation of multiple inhibitory receptors, progressive loss of effector function and impaired differentiation of memory T cells, etc. IRF4 plays critical roles in the generation of various immunosuppressive cells, and the above crosstalk between myeloid derived immunosuppressive cells and effector T cells (A–C) and Treg cells (a-c) in the TME. The black arrow indicates promotion, the black horizontal line indicates inhibition, and the red cross indicates that the anti-tumor activity of effector T cells is impaired.