Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy

Abstract

Natural killer (NK) cells, a crucial component of the innate immune system, have long been of clinical interest for their antitumor properties. Almost every aspect of NK cell immunity is regulated by interleukin-15 (IL-15), a cytokine in the common γ-chain family. Several current clinical trials are using IL-15 or its analogs to treat various cancers. Moreover, NK cells are being genetically modified to produce membrane-bound or secretory IL-15. Here, we discuss the key role of IL-15 signaling in NK cell immunity and provide an up-to-date overview of IL-15 in NK cell therapy.

Keywords: CAR NK cells; cancer immunotherapy; interleukin-15; natural killer cells.

Figure 1.. Timeline and major milestones in IL-15 and NK cell studies.

Abbreviations: CAR, chimeric antigen receptor; sIL-15, soluble IL-15; UCB, umbilical cord blood. Created with Biorender.com

Key Figure, Figure 2.. Intracellular checkpoint of IL-15 signaling in human or murine NK cells.

IL-15 binds to the IL-15Rα expressed on antigen-presenting cells and then is presented in trans to IL-2/IL-15Rβγ heterodimer on NK cells [12]. IL-15 induces activation of JAK1/STAT3 via the β chain and JAK3/STAT5 via the γ chain [–99]. Phosphorylated STAT3 and STAT5 proteins translocate to the nucleus where they activate transcription of the anti-apoptotic proteins BCL-2 [100] and MCL-1[101] and the oncogene c-Myc [102,103]. Activated adaptor protein Shc promotes Gab2 phosphorylation through the adaptor Grb2, and then induces the activation of PI3K-AKT-mTOR signaling [131]. XBP1 is induced by AKT and translocates to the nucleus, where it promotes GZMB expression [108]. mTORC1 drives the E4BP4-Eomes-CD122 pathway [132,133]. The third RAS-RAF-MAPK pathway induces the activation of c-Fos, c-Jun, and c-Myc, which promote NK cell proliferation [103]. There are also some intracellular checkpoints that negatively regulate IL-15 signaling. CIS interacts with JAK1 and inhibits its enzymatic activity [73]. ZHX2 blocks STAT5 activation [85]. SOCS-2 inhibits STAT5 phosphorylation [71]. OTUB1 inhibits AKT phosphorylation [81]. TIPE2 suppresses mTOR activity [83]. Foxo1 binds to the Tbx21 promoter and inhibits T-bet transcription [80]. Abbreviations: JAK, Janus kinase; STAT, signal transducer and activator of transcription; XBP1, X-box binding protein 1; GZMB, granzyme B; E4BP4, E4 promoter-binding protein 4; Eomes, eomesodermin; CIS, cytokine-inducible Src homology 2–containing protein; ZHX2, zinc fingers and homeoboxes; OTUB1, OTU domain-containing ubiquitin aldehyde-binding protein 1; TIPE2, tumor necrosis factor–α–induced protein-8 like-2; Foxo1, forkhead box o1. Created with Biorender.com

Figure I. in Box 3. IL-15 agonists and fusion proteins.

Top row, left to right: RLI is a fusion protein consisting of IL-15 linked to the cytokine binding (sushi) domain of IL-15Rα [116,117]. N-803 is an IL-15 complex comprising mutated IL-15 (N72D) linked to the sushi domain of IL-15Rα fused to human immunoglobulin IgG1 Fc [47,118]. Anti-GD2-RLI is a fusion protein comprising RLI and the heavy chain of an anti-GD2 ganglioside antibody [119,120]. 2B8T2M is a fusion protein consisting of N-803 and anti-CD20 [121]. N-809 is N-803 fused to an anti-PD-L1 antibody [122,123]. IL-15 trispecific killer engager (TriKE) is an engager containing CD16 and CD33 single-chain variable fragments (scFv) and hIL-15 linked by a fragment encoding G4S linker [124]. Anti-hPD1-IL15m is an IL-15 mutein fused with a human PD1-specific antibody [125]. dsNKG2D–IL-15 consists of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker [126]. HCW9201 is a heteromeric fusion protein complex comprising IL-12, IL-15, and IL-18 [127]. HCW9207 is a heteromeric fusion protein complex containing IL-12, IL-15, IL-18, and a CD16 ligation domain [127]. Pro-IL-15 is the extracellular domain of IL-15Rβ fused into the N terminus of IL-15-IL-15Rα-Fc through a tumor-enriched matrix metalloproteinase cleavable peptide linker [34]. Created with Biorender.com