Interleukin-15 and cancer: some solved and many unsolved questions

Abstract

Soluble interleukin (IL)-15 exists under two forms: as monomer (sIL-15) or as heterodimeric complex in association with sIL-15Rα (sIL-15/IL-15Rα). Both forms have been successfully tested in experimental tumor murine models and are currently undergoing investigation in phase I/II clinical trials. Despite more than 20 years research on IL-15, some controversial issues remain to be addressed. A first point concerns the detection of the sIL-15/IL-15Rα in plasma of healthy donors or patients with cancer and its biological significance. The second and third unsolved question regards the protumorigenic role of the IL-15/IL-15Rα complex in human cancer and the detrimental immunological consequences associated to prolonged exposure of natural killer (NK) cells to both forms of soluble IL-15, respectively. Data suggest that in vivo prolonged or repeated exposure to monomeric sIL-15 or the soluble complex may lead to NK hypo-responsiveness through the expansion of the CD8+/CD44+ T cell subset that would suppress NK cell functions. In vitro experiments indicate that soluble complex and monomeric IL-15 may cause NK hyporesponsiveness through a direct effect caused by their prolonged stimulation, suggesting that this mechanism could also be effective in vivo. Therefore, a better knowledge of IL-15 and a more appropriate use of both its soluble forms, in terms of concentrations and time of exposure, are essential in order to improve their therapeutic use. In cancer, the overproduction of sIL-15/IL-15Rα could represent a novel mechanism of immune escape. The soluble complex may act as a decoy cytokine unable to efficiently foster NK cells, or could induce NK hyporesponsiveness through an excessive and prolonged stimulation depending on the type of IL-15Rα isoforms associated. All these unsolved questions are not merely limited to the knowledge of IL-15 pathophysiology, but are crucial also for the therapeutic use of this cytokine. Therefore, in this review, we will discuss key unanswered issues on the heterogeneity and biological significance of IL-15 isoforms, analyzing both their cancer-related biological functions and their therapeutic implications.

piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells

“…The targeted delivery of IL-15 to NK cells may also be important clinically for an improved safety profile. 37 …”

“… 35 Since interleukin (IL)-15 is the main homeostatic cytokine required for NK cell differentiation, survival, proliferation, activation, and functionality, 36 it has been explored clinically to enhance the in vivo persistence and antitumor activity of donor NK cell products. 6 , 37 Concerns have been raised that the prolonged in vivo exposure to injected exogenous IL-15 may stimulate the expansion of CD8-positive T cells to reject donor NK cells or suppress NK cell function. 37 , 38 A strategy that may address the concerns has been developed to include IL-15 in an anti-CD19 CAR construct to ectopically produce IL-15 for autocrine stimulation of CAR-NK cells.…”

“… 6 , 37 Concerns have been raised that the prolonged in vivo exposure to injected exogenous IL-15 may stimulate the expansion of CD8-positive T cells to reject donor NK cells or suppress NK cell function. 37 , 38 A strategy that may address the concerns has been developed to include IL-15 in an anti-CD19 CAR construct to ectopically produce IL-15 for autocrine stimulation of CAR-NK cells. 18 , 38 , 39 …”

Monocytic Myeloid-Derived Suppressor Cells Inhibit Myofibroblastic Differentiation in Mesenchymal Stem Cells Through IL-15 Secretion

“…However, there must be other cytokines in M-MDSC supernatant that impair myofibroblastic differentiation. In addition, some studies suggest that the membrane-bound form but not the soluble form of IL-15 is the dominant physiological isoform of the cytokine ( Fiore et al, 2020 ). These findings may explain why the inhibitory effect of exogenous IL-15 is less than that of M-MDSC supernatant.…”

Protective and Therapeutic Effects of an IL-15:IL-15Rα-Secreting Cell-Based Cancer Vaccine Using a Baculovirus System

“…Increased IL-15 has been found in many autoimmune diseases, and the transgenic overexpression of IL-15 leads to leukemia in mice [16]. Administration of exogenous IL-15 might cause systemic toxicity in humans and mice by hyperproliferation of activated NK cells and escalation of plasma IFN-γ [51][52][53]. Therefore, we determined the working doses of the BacMam-based cancer vaccine for mice by conducting a doseresponse study and the cell concentration that produced the optimum level of IL-15:IL-15Rα was selected for further experiments.…”