Tethering IL2 to Its Receptor IL2Rβ Enhances Antitumor Activity and Expansion of Natural Killer NK92 Cells

IL2 is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). IL2 signaling is mediated through interactions with a multi-subunit receptor complex containing IL2R alpha, IL2R beta, and IL2R gamma. Adult natural killer (NK) cells express only IL2R beta and IL2R gamma subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2R beta fusion protein of IL2 and its receptor IL2R beta joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared with an IL2-secreting NK92 cell line, NK92CIRB were more activated, cytotoxic, and resistant to growth inhibition. Direct contact with cancer cells enhanced the cytotoxic character of NK92CIRB cells, which displayed superior in vivo antitumor effects in mice. Overall, our results showed how tethering IL2 to its receptor IL2R beta eliminates the need for IL2R alpha and IL2R beta, offering a new tool to selectively activate and empower immune therapy. (C) 2017 AACR.