The Yin and Yang aspects of IL-27 in induction of cancer-specific T-cell responses and immunotherapy

Abstract

Accumulating evidences from animal studies have indicated that both endogenous and exogenous IL-27, an IL-12 family of cytokine, can increase antitumor T-cell activities and inhibit tumor growth. IL-27 can modulate Treg responses, and program effector T cells into a unique T-effector stem cell (TSEC) phenotype, which enhances T-cell survival in the tumor microenvironment. However, animal studies also suggest that IL-27 induces molecular pathways such as IL-10, PD-L1 and CD39, which may downregulate tumor-specific T-cell responses. In this review paper, we will discuss the Yin and Yang aspects of IL-27 in the induction of tumor-specific T-cell responses, and the potential impacts of these functions of IL-27 in the design of cancer immunotherapy.

Keywords: IL-12; IL-27; T-effector stem cells; cancer immunotherapy; regulatory T cells.

Figure 1. Role of IL-27 in induction T-effector stem cells

During T-cell activation, signals through T-cell receptor (signal 1) and co-stimulatory molecules (signal 2) result in tumor-specific T-cell activation and differentiation, while IL-27 signaling activates both Stat1 and Stat3, leading to the expression of gene products that program tumor-specific T cells into a unique effector stem cell phenotype.

Figure 2. Role of IL-27 in the modulation of Treg responses

IL-27 can modulate Treg responses in the following three ways: inhibiting IL-2 production by T_NA, which affects Treg homeostasis; inhibiting the conversion of T_N into inducible Treg cells; and promoting Treg cells (inducible Treg cells and nTreg) to differentiate into Th1-Treg cells that express IL-10 and IFN-γ. T_N: Naive T cells; T_NA: Newly activated T cells.

Figure 3. IL-27-induced pathways that may downregulate T-cell responses

IL-27 signaling in DC induces CD39 expression, which can induce Treg cells expressing CD69 and CD39; IL-27 signaling in Treg cell promotes Th1-Treg cell development. Finally, IL-27 signaling in T cells promotes T-cell expression of PD-L1 and IL-10. DC: Dendritic cell.

Figure 4. The antitumor versus protumor effects of IL-27

The roles of IL-27 in stimulating Th1/Tc1 response, enhancing T-cell survival/expansion, inhibiting Treg homeostasis and inhibiting inflammation represent its antitumor effect; while IL-27 induction of CD39, PD-L1 and IL-10 and promotion of Th1-Treg response may have protumor effect. Studies using various tumor models have revealed that IL-27-mediated antitumor effects are dominant over its protumor effects. DC: Dendritic cell.