T(H)17 cells in tumour immunity and immunotherapy

Abstract

T helper 17 (T(H)17) cells have well-described roles in autoimmune disease. Recent evidence suggests that this effector T cell subset is also involved in tumour immunology and may be a target for cancer therapy. In this Review, we summarize recent findings regarding the nature and relevance of T(H)17 cells in mouse models of cancer and human disease. We describe the interplay between T(H)17 cells and other immune cells in the tumour microenvironment, and we assess both the potential antitumorigenic and pro-tumorigenic activities of T(H)17 cells and their associated cytokines. Understanding the nature of T(H)17 cell responses in the tumour microenvironment will be important for the design of more efficacious cancer immunotherapies.

Figure 1. Differentiation of helper T cell subsets

Following activation by antigen-presenting cells such as dendritic cells (DCs), naive CD4⁺ T cells can be polarized into different effector T cell subsets — T helper 1 (T_H1), T_H2, T_H17 and regulatory T (T_Reg) cells — depending on the local cytokine environment. The differentiation of each of these effector T cell subsets is controlled by distinct sets of transcription factors. In the presence of interleukin-6 (IL-6) and transforming growth factor-β (TGFβ), naive T cells can differentiate into T_H17 cells, which are characterized by expression of the transcription factors retinoic acid receptor-related orphan receptor-γt (RORγt) and signal transducer and activator of transcription 3 (STAT3). Furthermore, IL-1 and IL-23 can promote and/or stabilize T_H17 cell differentiation and expansion. FOXP3, forkhead box P3; GATA3, GATA-binding protein 3; IFNγ, interferon-γ; TCR, T cell receptor.

Figure 2. T_H17 cells and antitumour immunity

T helper 17 (T_H17) cells traffic to the tumour microenvironment and are expanded by antigen-presenting cells, such as myeloid dendritic cells (DCs) through interleukin-1 (IL-1) and IL-23. T_H17 cells promote the trafficking and retention of effector T cells and natural killer (NK) cells in the tumour environment, through inducing the production of the chemokines CXC-chemokine ligand 9 (CXCL9) and CXCL10 by primary tumour cells. In addition, T_H17 cells induce the production of CC-chemokine ligand 20 (CCL20) by tumour cells and this leads to the recruitment of CC-chemokine receptor 6 (CCR6)⁺ DCs. Therefore T_H17 cells can promote protective antitumour immunity by inducing the recruitment of pro-inflammatory immune effector cells; TCR, T cell receptor.