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Sumei Chen,1,* Lingrong Yang,2,* Bing Xia,3 Haitao Zhu,4 Zhenghao Piao,5 Youssef Jounaidi6 1Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 2Department of Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 3Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 4Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of China; 5Department of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People’s Republic of China; 6Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA*These authors contributed equally to this workCorrespondence: Youssef Jounaidi, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA, Email yjounaidi@mgh.harvard.eduBackground: Enhancing NK cells’ antitumor activity requires sustained cytokine signaling. Interleukin-15 (IL-15) is a potent immunostimulatory cytokine used to armor CAR-NK and CAR-T cell immunotherapies. However, strategies to increase IL-15 expression and antitumor effect may trigger systemic toxicity with the potential to promote oncogenesis and autoimmune diseases.Methods: To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.Results: NK92-expressing IL15RB (NK92IL15RB) cells expand indefinitely without exogenous cytokines and have significantly higher anticancer activity than NK-92 stimulated by IL-15, IL-2, or expressing tethered IL-2. NK92IL5RB showed resistance to irradiation and IL-4. However, TGFβ 1 substantially reduced NK92IL5RB killing, suggesting the need to inhibit TGFβ 1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92IL15RB cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92IL15RB antitumor activity against leukemia and increased its STAT5 activation. NK92IL15RB anti-tumors activity was further enhanced by combination with anti-PD1.Conclusion: Our data suggest that the tethering of IL-15 to its receptor IL2Rβ empowers NK cell cytolytic activity. Additionally, the tethering of IL-15 will prevent any systemic risk of toxicity.Keywords: IL-15, IL2RB receptor, natural killer cells, cancer immunotherapy, IL15RB |
