{"title":"增强癌症免疫疗法的自激活 IL-15 嵌合细胞因子受体。","authors":"Sumei Chen, Lingrong Yang, Bing Xia, Haitao Zhu, Zhenghao Piao, Youssef Jounaidi","doi":"10.2147/ITT.S490498","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.</p><p><strong>Results: </strong>NK92-expressing IL15RB (NK92<sup>IL15RB</sup>) 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. NK92<sup>IL5RB</sup> showed resistance to irradiation and IL-4. However, TGFβ1 substantially reduced NK92<sup>IL5RB</sup> killing, suggesting the need to inhibit TGFβ1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92<sup>IL15RB</sup> cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92<sup>IL15RB</sup> antitumor activity against leukemia and increased its STAT5 activation. NK92<sup>IL15RB</sup> anti-tumors activity was further enhanced by combination with anti-PD1.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":null,"pages":null},"PeriodicalIF":6.2000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472742/pdf/","citationCount":"0","resultStr":"{\"title\":\"A Self-Activating IL-15 Chimeric Cytokine Receptor to Empower Cancer Immunotherapy.\",\"authors\":\"Sumei Chen, Lingrong Yang, Bing Xia, Haitao Zhu, Zhenghao Piao, Youssef Jounaidi\",\"doi\":\"10.2147/ITT.S490498\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.</p><p><strong>Results: </strong>NK92-expressing IL15RB (NK92<sup>IL15RB</sup>) 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. NK92<sup>IL5RB</sup> showed resistance to irradiation and IL-4. However, TGFβ1 substantially reduced NK92<sup>IL5RB</sup> killing, suggesting the need to inhibit TGFβ1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92<sup>IL15RB</sup> cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92<sup>IL15RB</sup> antitumor activity against leukemia and increased its STAT5 activation. NK92<sup>IL15RB</sup> anti-tumors activity was further enhanced by combination with anti-PD1.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":30986,\"journal\":{\"name\":\"ImmunoTargets and Therapy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.2000,\"publicationDate\":\"2024-10-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472742/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ImmunoTargets and Therapy\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2147/ITT.S490498\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ImmunoTargets and Therapy","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2147/ITT.S490498","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
A Self-Activating IL-15 Chimeric Cytokine Receptor to Empower Cancer Immunotherapy.
Background: 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, TGFβ1 substantially reduced NK92IL5RB killing, suggesting the need to inhibit TGFβ1 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.
期刊介绍：
Immuno Targets and Therapy is an international, peer-reviewed open access journal focusing on the immunological basis of diseases, potential targets for immune based therapy and treatment protocols employed to improve patient management. Basic immunology and physiology of the immune system in health, and disease will be also covered.In addition, the journal will focus on the impact of management programs and new therapeutic agents and protocols on patient perspectives such as quality of life, adherence and satisfaction.
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