Jounaidi et al. created a chimeric IL2-IL2Rβ fusion protein (CIRB) that acts like constitutively activated IL2Rβ. NK92 cells expressing CIRB were independent of exogenous IL2, showed signs of increased activation and cytotoxicity compared to parental or IL2-secreting NK92 cells, were resistant to immunosuppressive TGFβ1, survived longer following irradiation, and showed superior persistence and antitumor efficacy in vivo. NK92CIRB cells also expressed higher levels of CD16, making them better effector cells for ADCC.
Interleukin-2 (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 IL2Ralpha, IL2Rbeta and IL2Rgamma. Adult natural killer (NK) cells express only IL2Rbeta and IL2Rgamma subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2Rbeta fusion protein of IL2 and its receptor IL2Rbeta joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared to 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 IL2Rbeta eliminates the need for IL2Ralpha and IL2Rbeta, offering a new tool to selectively activate and empower immune therapy.
Author Info: (1) Anesthesia, Massachusetts General Hospital yjounaidi@mgh.harvard.edu. (2) Massachusetts General Hospital. (3) Anesthesia, Massachusetts General Hospital. (4) Massachusetts Gene
Author Info: (1) Anesthesia, Massachusetts General Hospital yjounaidi@mgh.harvard.edu. (2) Massachusetts General Hospital. (3) Anesthesia, Massachusetts General Hospital. (4) Massachusetts General Hospital.
