Cancer immunotherapy with T-cell targeting cytokines: IL-2 and IL-7

Abstract

Clinical trials have demonstrated that an increased number of effector cells, especially tumor-specific T cells, is positively linked with patients' prognosis. Although the discovery of checkpoint inhibitors (CPIs) has led to encouraging progress in cancer immunotherapy, the lack of either T cells or targets for CPIs is a limitation for patients with poor prognosis. Since interleukin (IL)-2 and IL-7 are cytokines that target many aspects of T-cell responses, they have been used to treat cancers. In this review, we focus on the basic biology of how these cytokines regulate T-cell response and on the clinical trials using the cytokines against cancer. Further, we introduce several recent studies that aim to improve cytokines' biological activities and find the strategy for combination with other therapeutics. [BMB Reports 2021; 54(1): 21-30].

Fig. 1

Modification of IL-2 for anticancer therapy. (A) Mutations in CD122 (IL-2Rβ)-binding regions of IL-2 superkines (Super-IL-2) increase binding affinity of IL-2 for IL-2Rβ than CD25 (IL-2Rα). (B) The conjugation with antibody to tumor-associated antigens (TAAs) or collagen-binding domain delivers IL-2 to tumor sites. (C) The IL-2 complex with a neutralizing antibody clone S4B6 predominantly targets cells expressing dimeric IL-2Rβγ. (D) Fc-fused IL-2 has a prolonged serum half-life. (E) Fc-fused mutant IL-2 shows an increased half-life with enhanced binding affinity for IL-2Rβ. (F) The conjugation of polyethylene glycol (PEG) shows increased IL-2 persistence with an inhibited IL-2Rα binding. Figure created with BioRender.com.

Fig. 2

Overview of CD8 T cell immunity regulated by IL-2 and IL-7. The receptor for IL-7 is expressed on the naïve and memory T cells including precursors cells; common lymphoid progenitors (CLP), double-positive, and single-positive thymocytes, and recent thymic emigrants (RTE). IL-7 is mainly produced by stromal cells and gives a signal to IL-7Rα-expressing cells to regulate their survival, proliferation, and maintenance. By contrast, the IL-2 receptors are highly induced on activated T cells after antigenic stimulation and the cells themselves also become a major producer of IL-2. After rapid expansion, the effector T cells develop into different fates depending on the amount of IL-2 signaling. Cells expressing high levels of IL-2Rα receive strong IL-2 signaling and become short-lived effector cells showing increased expression of Blimp1, KLRG1, and cytolytic activity. Cells expressing low levels of IL-2Rα receive relatively weak IL-2 signaling and become memory precursor cells showing increased expression of IL-7Rα, CD62L, IL-2 production, and proliferation capacity but decreased expressions of effector-associated molecules above. The re-expression of IL-7Rα on memory T cells capable of maintaining the long-term survival of the cells.

Fig. 3

Modification of IL-7 for anticancer therapy. (A) Adjuvant treatment of IL-7 and its receptor complex enhances the potency of cancer vaccines. (B) Intratumoral administration of IL-7-transduced DCs (DC-AdIL-7) induces direct IL-7 signals in the tumor site. (C-F) Engineered IL-7 complexes with enhanced bioactivity. (C) IL-7 complexed with IL-7Rα-Fc. (D) IL-7 complex with a monoclonal antibody clone M25. (E) IL-7 fused with the Fc region of the antibody. (F) IL-7 fused to a hybrid Fc (IgD/IgG4) has a prolonged serum half-life without cytotoxicity on target cells. Figure created with BioRender.com.