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Review
. 2021 Feb 17;13(4):837.
doi: 10.3390/cancers13040837.

Heterodimeric IL-15 in Cancer Immunotherapy

Cristina Bergamaschi  1 , Vasiliki Stravokefalou  2 , Dimitris Stellas  2 , Sevasti Karaliota  2   3 , Barbara K Felber  1 , George N Pavlakis  2
Affiliations
Review

Heterodimeric IL-15 in Cancer Immunotherapy

Cristina Bergamaschi et al. Cancers (Basel). .

Abstract

Immunotherapy has emerged as a valuable strategy for the treatment of many cancer types. Interleukin-15 (IL-15) promotes the growth and function of cytotoxic CD8+ T and natural killer (NK) cells. It also enhances leukocyte trafficking and stimulates tumor-infiltrating lymphocytes expansion and activity. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and the so-called IL-15 receptor alpha chain that are together termed "heterodimeric IL-15" (hetIL-15). hetIL-15, closely resembling the natural form of the cytokine produced in vivo, and IL-15:IL-15Rα complex variants, such as hetIL-15Fc, N-803 and RLI, are the currently available IL-15 agents. These molecules have showed favorable pharmacokinetics and biological function in vivo in comparison to single-chain recombinant IL-15. Preclinical animal studies have supported their anti-tumor activity, suggesting IL-15 as a general method to convert "cold" tumors into "hot", by promoting tumor lymphocyte infiltration. In clinical trials, IL-15-based therapies are overall well-tolerated and result in the expansion and activation of NK and memory CD8+ T cells. Combinations with other immunotherapies are being investigated to improve the anti-tumor efficacy of IL-15 agents in the clinic.

Keywords: IL-15; IL-15 receptor alpha (IL-15Rα); cancer immunotherapy; clinical trials; cytokine; cytotoxic cells; heterodimeric IL-15 (hetIL-15).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of hetIL-15 production. IL-15 is a heterodimeric cytokine, comprising the IL-15 and IL-15Rα chains that are together termed heterodimeric IL-15 (hetIL-15). Simultaneous expression of IL-15Rα in the same cells (dendritic cells, monocyte/macrophages, and others) is necessary for the production and secretion of IL-15 under physiological conditions. Upon co-expression, the two chains, IL-15 and IL-15Rα, associate in the endoplasmic reticulum (ER), due to their high binding affinity (Kd = 10−11 M). The IL-15 heterodimer is then transported to the cell surface and released as a bioactive soluble heterodimeric molecule, upon proteolytic cleavage of IL-15Rα.
Figure 2
Figure 2
Different IL-15 preparations used in cancer immunotherapy. The single-chain E. coli-derived IL-15 (sch rhIL-15, left) [53] is the first IL-15 tested in the clinic, but its use is limited by the short half-life and potential toxicity. The natural form of IL-15 produced physiologically is the heterodimer of IL-15 with IL-15Rα. Several heterodimeric forms have been developed. From left to right, human embryonic kidney 293 (HEK293)-derived or Chinese hamster ovary (CHO)-derived hetIL-15/NIZ985, the soluble heterodimer of IL-15 with IL-15Rα, upon natural shedding of IL-15Rα from the membrane of producing cells [54]; human HEK293-derived hetIL-15FC, a dimeric form in which soluble IL-15Rα is fused to the Fc region of IgG1; N-803, also known as Anktiva and ALT-803, consisting of a CHO-derived soluble complex comprising mutated IL-15 (IL-15 N72D) and a dimeric IL-15Rα sushi domain-IgG1 Fc fusion protein [55]; Receptor-Linker-IL-15 (RLI) consists of the IL-15Rα sushi domain fused to IL-15, via a 20-amino acid flexible linker [56].
Figure 3
Figure 3
Mechanism of anti-tumor activity of heterodimeric IL-15. hetIL-15 therapy is beneficial against both primary tumor and metastatic disease. Use of hetIL-15 is a general method to push effector lymphocytes inside the tumor. IL-15 directly stimulates the cytotoxicity (granzyme B, red dots) and IFN-γ production (green dots) of CD8+ T and NK cells in the tumor microenvironment. IL-15 also induces the secretion of XCL1 (blue dots) from activated lymphocytes, a chemokine responsible for the recruitment of XCR1+ conventional dendritic cells (cDC) with cross-priming ability. cDC within the tumor support CD8+ T cells effector function and secretes Chemokine (C-X-C motif) ligand 9 (CXCL9) and Chemokine (C-X-C motif) ligand 10 (CXCL10) (black dots) in response to IFN-γ. CXCL9 and CXCL10 create a gradient that attracts more CXCR3+ effector CD8+ T and NK cells. As a result, the number of CD8+ T and NK cells, as well as the CD8/Treg ratio, increase in hetIL-15-treated tumors, leading to tumor growth control.
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