Th17 cells in cancer: the ultimate identity crisis

Abstract

T helper 17 (Th17) cells play a complex and controversial role in tumor immunity and have been found to exhibit a fluctuating identity within the context of cancer. The recent, expanding literature on these cells attests to their puzzling nature, either promoting or suppressing tumor growth depending on the malignancy and course of therapeutic intervention investigated. This review addresses several newly appreciated factors that may help delineate Th17 cells' immunological properties in the context of cancer. Several reports suggest that inflammatory signals induced in the tumor milieu regulate the functional fate and antitumor activity of Th17 cells. Recent findings also point to significant alterations in Th17 cells due to their interplay with regulatory T lymphocytes and cytotoxic CD8(+) T cells within the tumor microenvironment. Finally, an appreciation for the stem cell-like properties of Th17 cells that augment their persistence and activity emerges from recent reports. The impact of these factors on Th17 cells' antitumor efficacy and how these factors may be exploited to improve cancer therapies will be discussed.

Keywords: IL-17A; RORγt; Th17; cancer; immunotherapy; plasticity; tumor microenvironment.

Figure 1

Differentiation of helper T cell subsets is determined by cytokines. In the presence of interleukin-6 (IL-6), IL-21, and transforming growth factor-beta (TGF-β), naïve CD4⁺ T cells differentiate into a Th17 cell phenotype, which is characterized by the expression of transcription factors retinoic acid receptor-related orphan receptor-γt (RORγt) and signal transducer and activator of transcription 3 (STAT3). IL-1β and IL-23 cytokines can promote and stabilize this phenotype during cell expansion. Once programed, these cells secrete IL-17A, IL-17F, IL-21, and IL-22, which play a key role in enhancing autoimmunity and host defense. Cytokines IL-12, IL-4, and TGF-β and transcription factors T-bet, GATA3, and FoxP3 have been shown to regulate Th1, Th2, and Treg cell development, respectively. These distinct subsets regulate immune response to foreign, self, and tumor antigens.

Figure 2

Culture conditions drive the expression of Th17 or non-classical Th1 cells. Cell surface receptors distinguish T helper subsets. (A) Th17 precursors can be identified from peripheral blood by the presence of lectin-like receptor CD161, chemokine receptor 6 (CCR6), and IL-23 receptor (IL-23R). In the presence of IL-1β and IL-23, these precursors differentiate into mature Th17 cells capable of IL-17A production and identified by the addition of CCR4 and IL-17 receptor E to their surface repertoire. In the presence of IL-23, the Th17 phenotype is maintained as seen with the preservation of all surface markers, IL-17A and RORγt. When cultured with IL-12, however, mature Th17 cells adopt a divergent phenotype that has both Th1 and Th17-like aspects. These cells, termed Th1/Th17 cells, express CXCR3 instead of CCR4, produce both IFN-γ as well as IL-17A, and have a high expression of RORγt with an intermediate expression of the Th1 transcription factor, T-bet. In the continued presence of IL-12, Th1/Th17 cells can adopt a Th1-like phenotype and are termed non-classical Th1 cells. As shown, non-classical Th1 cells have an increased expression of T-bet, decreased RORγt, and produce only IFN-γ. (B) Classical Th1 cells are directly derived from naïve CD4⁺ T cells in the presence of IL-12 and can be identified through the expression of CXCR3, IFN-γ, and T-bet.

Figure 3

Cytokines determine the effector versus regulatory nature of Th17 cells in tumor immunity. Cytokines and costimulatory molecules distinctly transform Th17 cells into either an effector or regulatory phenotype, which in turn regulates immunity to self/tumor tissue. (A) Effector Th17 cells activated with IL-1β, IL-23, IL-6, IL-12 and/or ICOS agonist are poly-functional and are capable of mediating potent antitumor immunity. (B) Regulatory Th17 cells programed with cytokines such as TGF-β, IL-2, and/or CTLA4 can dampen their function and persistence, thereby potentially reducing their capacity to kill tumors. Regulatory Th17 cells likely do not foster the induction or cooperation of CTLs to the malignant site.

Figure 4

TGF-β induces Th17 cells to express ectonucleotidases and release immunosuppressive adenosine. (A) Th17 cells programed with TGF-β and IL-6 fail to secrete IFN-γ but do secrete IL-17A and IL-10. These cells expressed nominal amounts of Gfi1 (growth factor independent protein 1 – repressor of ectonucleotidase), resulting in CD39 and CD73 ectonucleotidase expression on their cell surface. CD39 and CD73 convert ATP to immunosuppressive adenosine, thereby contributing to the inhibition of antitumor immunity. (B) Conversely, programing CD4⁺ T cells in the absence of TGF-β but presence of IL-1β, IL-6 and IL-23 supports the generation of Th17 cells that secrete IL-17A and express RORγt and STAT3. Moreover, these cells also express transcription factor Tbx21 and co-secrete IL-17 and IFN-γ but not the immunosuppressive cytokine IL-10. These inflammatory Th17 cells also express increased Gfi1. It is also possible that they express CD26, which facilitates the conversion of adenosine to inosine upon binding of adenosine deaminase (ADA). These infused cells promote the activation of CD8⁺ effector T cells and cooperate to mediate tumor regression in an IFN-γ and IL-17A-dependent manner.

Figure 5

Divergent potential for self-renewal and plasticity in T cell subsets. Over time, the majority of CD4⁺ T cells differentiate into terminally differentiated effectors that possess short-lived immune responses to tumor antigen. However, a small proportion of these cells will enter into a self-renewing pool, resulting in the generation of long-lived memory T cells. Th17 cells appear to exist in a progenitor-like stage (A; Th17 precursor) compared to Th1 or Th0 cells (B and C, respectively). Th17 cells possess a number of uniquely exciting traits: enhanced self-renewal, multi-functionality and rapid recall responses to tumor antigen.

Figure 6

Bach2 inhibits T-effector differentiation and stabilizes Tregs. Cytokines present in the environment regulate the phenotypic and functional fate of T cells. The combination of IL-2 and TGF-β creates an environment conducive for the generation of inducible Treg cells. (A) WT cells differentiated into FoxP3⁺ Treg cells when cultured with these cytokines, while Bach2 knockout cells converted into effector T cells. This suggests that Bach2 is (B) an instrumental regulator of the immune system through (C) inhibition of effector function and thereby, stabilization of Tregs.