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Review
. 2024 Sep;56(9):1900-1908.
doi: 10.1038/s12276-024-01301-3. Epub 2024 Sep 2.

Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends

Se Jin Im  1 , Kyungmin Lee  2 , Sang-Jun Ha  3
Affiliations
Review

Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends

Se Jin Im et al. Exp Mol Med. 2024 Sep.

Abstract

IL-2 therapy, which enhances the function of CD8 + T cells, was initially employed as the cornerstone of immunotherapy against cancer. However, the impact of this therapy extends beyond CD8 + T cells to cells expressing IL-2R, such as endothelial cells and regulatory T cells (Tregs), resulting in various side effects. Consequently, IL-2 therapy has taken a step back from the forefront of treatment. Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies and CTLA-4 antibodies, are used because of their durable therapeutic responses and the reduced incidence of side effects. Nevertheless, only a small fraction of cancer patients respond to ICIs, and research on IL-2 as a combination treatment to improve the efficacy of these ICIs is ongoing. To mitigate side effects, efforts have focused on developing IL-2 variants that do not strongly bind to cells expressing IL-2Rα and favor signaling through IL-2Rβγ. However, recent studies have suggested that, in the context of persistent antigen stimulation models, effective stimulation of antigen-specific exhausted CD8 + T cells in combination with PD-1 inhibitors requires either 1) binding to IL-2Rα or 2) delivery via a fusion with PD-1. This review explores the historical context of IL-2 as an immunotherapeutic agent and discusses future directions for its use in cancer immunotherapy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Importance of stem-like T cells and their differentiation in response to PD-1- and PD-1/IL-2-directed immunotherapies.
a When naive T cells encounter a high antigen load, they differentiate into stem-like T cells and 1st effector cells. While 1st effector cells exhibit strong cytolytic capabilities, they eventually disappear through activation-induced cell death. In contrast, stem-like T cells sustain themselves through self-renewal and maintain antigen-specific T-cell responses by generating a transitory population and terminally exhausted CD8 T cells in response to antigenic stimulation. b Upon PD-1 blockade, only stem-like T cells proliferate and give rise to a substantial number of transitory cells with high cytolytic activity, thereby mediating antiviral and antitumor responses. c Combination therapy involving anti-PD-1 antibodies and IL-2 treatment also results in the exclusive proliferation of stem-like T cells. In contrast to the canonical differentiation pathway of exhausted CD8 T cells, stem-like T cells generate better effectors. d The better effectors generated by the combination therapy of IL-2 and PD-1 blockade exhibited effector-like features compared to terminally exhausted CD8 + T cells. These include decreased expression of inhibitory receptors (PD-1 and Tim-3) and increased expression of effector molecules (granzymes and perforin), inflammatory cytokines (IFNγ, TNFα, and IL-2), and memory markers (IL-7R and Lef1). e IL-2R-mediated signals activate STAT5, which enhances the effector functions of exhausted CD8 + T cells and antagonizes Tox, resulting in mitigated exhaustion.
Fig. 2
Fig. 2. Configuration of IL-2R and engineered IL-2 to avoid binding to IL-2Rα.
a IL-2R variants include the intermediate-affinity IL-2R, which is composed of CD122 and CD132 and is associated with naive, memory, and exhausted CD8 + T cells. In contrast, the high-affinity IL-2R includes the CD25 subunit alongside CD122 and CD132, which are predominantly found on activated CD8 and regulatory T cells. b Engineered IL-2 variants are shown. The panel illustrates the modification of IL-2 to selectively avoid binding to IL-2Rα, thereby enhancing therapeutic efficacy and minimizing side effects. The IL-2 mutein is a mutant version that does not bind to the trimeric high-affinity IL-2R. PEGylated IL-2, which is conjugated with PEG, has a prolonged half-life and decreases the affinity for trimeric IL-2R. IL-2/anti-IL2 antibody immune complexes are designed to increase the half-life and selectively target specific IL-2 receptors. The IL-2-CD25 fusion protein preferentially binds to dimeric intermediate-affinity IL-2R.
Fig. 3
Fig. 3. Mode of action of IL-2 derivatives and the requirement for PD-1 blockade in cancer immunotherapy.
a In IL-2wt + PD-1 blockade, combination therapy with IL-2wt and PD-1-directed immunotherapy leads to an increase in IL-2Rα expression on stem-like T cells and the generation of a large number of better effectors. The addition of anti-PD-1/PD-L1 antibodies further enhances the cytolytic activity of the effectors, thereby effectively suppressing tumor growth. b In IL-2v + PD-1 blockade, IL-2v, which is engineered to avoid binding to IL-2Rα, preferentially binds to PD-1neg T cells expressing the IL-2Rβγ dimeric receptor, thereby mediating their expansion. However, since PD-1neg cells, which do not bind to anti-PD-1 antibodies, are mostly tumor nonspecific, IL-2v combined with PD-1 blockade exhibits minimal anticancer efficacy. c The PD1-IL2v fusion protein acts as follows: the anti-PD-1 and IL-2v fusion protein delivers IL-2v to PD-1+ stem-like T cells, thus enabling the generation of better effectors. Additionally, the anti-PD-1 portion hampers the PD-1/PD-L1 interaction, thus enabling the effectors to exhibit strong cytolytic activity. d IL-2wt alone acts as follows: IL-2wt administration upregulated IL-2Rα expression on stem-like T cells, thereby facilitating enhanced binding with IL-2 and the generation of a large number of better effectors. However, because the PD-1/PD-L1 interaction still occurs, this interaction continues to inhibit the cytolytic function of the effectors, leading to continued tumor growth.
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