The Role of IL-7 and IL-7R in Cancer Pathophysiology and Immunotherapy

Abstract

Interleukin-7 (IL-7) is a multipotent cytokine that maintains the homeostasis of the immune system. IL-7 plays a vital role in T-cell development, proliferation, and differentiation, as well as in B cell maturation through the activation of the IL-7 receptor (IL-7R). IL-7 is closely associated with tumor development and has been used in cancer clinical research and therapy. In this review, we first summarize the roles of IL-7 and IL-7Rα and their downstream signaling pathways in immunity and cancer. Furthermore, we summarize and discuss the recent advances in the use of IL-7 and IL-7Rα as cancer immunotherapy tools and highlight their potential for therapeutic applications. This review will help in the development of cancer immunotherapy regimens based on IL-7 and IL-7Rα, and will also advance their exploitation as more effective and safe immunotherapy tools.

Keywords: IL-7; IL-7R signal; cancer; immunotherapy.

Figure 1

Transduction of IL-7 signaling pathway. IL-7 induces the activation of IL-7R downstream signaling pathway kinases, including JAK1 (linked to IL-7Rα) and JAK3 (linked to common γC), STAT1, STAT3, STAT5, PI3K, AKT, and MAPK. IL-7 signal transduction promotes cell proliferation and survival and inhibits apoptosis by regulating gene expression levels in the nucleus, including a decrease in pro-apoptotic factors (such as Bad and Bax) and cell cycle inhibitors (p21^CIP1 and p27^KIP1) and an increase in anti-apoptotic factors (such as Bcl-XL, Bcl-2, and McL-1) and glucose metabolism regulators (Glut1, HXKⅡ).

Figure 2

IL-7 and IL-7R have both pro- and anti-tumor functions. IL-7 plays anti-tumor roles by regulating immune cells to release cytokines such as IFN-γ, IL-1β, IL-1α and TNF-α. In contrast, IL-7 can promote the proliferation and survival of tumor cells by binding to the IL-7R to active JAK/STAT5, the PI3K/AKT and Ras/ERK signaling pathways to regulate gene expression levels of Bcl-2, Bcl-XL, CyclinA, CyclinD2, and p27^kip.

Figure 3

Application of IL-7 and IL-7R in cancer immunotherapy. (A) Recombinant IL-7 administration. (B) Combination use of IL-7. (C) CAR-T and TCR T cell expressed IL-7. (D) CAR-T expressing engineered IL-7R or C7R. (E) CTL expressed engineered IL-7R. (F) Anti-IL-7R monoclonal antibodies. (G) IL-7R pathway signaling inhibitors.