20: Heterodimeric IL-15 regulates the balance of effector and regulatory cells, favoring anti-tumor responses

20: Heterodimeric IL-15 regulates the balance of effector and regulatory cells, favoring anti-tumor responses

The common γ-chain cytokine interleukin-15 (IL-15) regulates immune homeostasis and the fate of many lymphocyte subsets, and holds potential in fighting infections and cancer. We have previously showed that co-expression of IL-15 and IL-15 Receptor alpha (IL-15Rα) in the same cell allows for efficient production and secretion of bioactive IL-15/IL-15Rα heterodimer, whereas single-chain IL-15 is unstable. This led to the hypothesis that the physiologically relevant molecule in vivo is the heterodimer. Consistent with this hypothesis, we determined that the IL-15 found in the plasma of mice and humans is the heterodimer. We have developed stable, clonal HEK293-derived human cell lines producing naturally processed and glycosylated IL-15/IL-15Rα heterodimers. Repeated subcutaneous administration of purified IL-15 heterodimers in macaques resulted in sustained plasma IL-15 levels and in dose-dependent expansion of NK and T cells in blood and tissues, demonstrating pharmacokinetics and in vivo bioactivity superior to monomer IL-15. Even at the dose of 50μg/kg, the cytokine was well tolerated with no major side effects. Interestingly, IL-15 heterodimer promotes the preferential expansion of CD8+NK and CD8+ and CD4+ effector T (Teffs) cells, without preferentially affecting Tregs. As result, sustained IL-15 levels are associated with lower relative frequency of Tregs and an increased ratio of Teffs/Tregs. Use of IL-15 heterodimers in the colon carcinoma mouse cancer model resulted in a significant delay in tumor growth, as a consequence of the infiltration of cytotoxic CD8+ T cells and the increase in the ratio Teff/Treg in the tumor environment. In conclusion, the favorable pharmacokinetic/pharmacodynamic profile of IL-15 heterodimer allows for lower dose, simple s.c. delivery, and lowers the possibility of toxicity due to cytokine spike. Preclinical cancer studies suggested that IL-15 heterodimer-based immunotherapy favors the development of anti-tumor responses by favoring cytotoxic over regulatory cells.

共同的γ链细胞因子白细胞介素 - 15（IL - 15）调节免疫稳态以及许多淋巴细胞亚群的命运，并且在对抗感染和癌症方面具有潜力。我们先前已经表明，IL - 15和IL - 15受体α（IL - 15Rα）在同一细胞中的共表达能够高效产生和分泌具有生物活性的IL - 15/IL - 15Rα异二聚体，而单链IL - 15是不稳定的。这导致了一种假设，即体内生理相关分子是异二聚体。与这一假设相符，我们确定在小鼠和人类血浆中发现的IL - 15是异二聚体。我们已经开发出稳定的、源自HEK293的克隆人类细胞系，其能够产生天然加工和糖基化的IL - 15/IL - 15Rα异二聚体。在猕猴中重复皮下给予纯化的IL - 15异二聚体导致血浆IL - 15水平持续升高，并且血液和组织中的NK细胞和T细胞呈剂量依赖性扩增，这表明其药代动力学和体内生物活性优于单体IL - 15。即使在50μg/kg的剂量下，该细胞因子也具有良好的耐受性，没有重大副作用。有趣的是，IL - 15异二聚体促进CD8⁺NK细胞以及CD8⁺和CD4⁺效应T（Teffs）细胞的优先扩增，而不会优先影响调节性T细胞（Tregs）。结果，持续的IL - 15水平与调节性T细胞的相对频率降低以及效应T细胞/调节性T细胞的比率增加有关。在结肠癌小鼠癌症模型中使用IL - 15异二聚体导致肿瘤生长显著延迟，这是由于细胞毒性CD8⁺T细胞的浸润以及肿瘤环境中效应T细胞/调节性T细胞比率的增加。总之，IL - 15异二聚体良好的药代动力学/药效学特性允许使用更低的剂量、简单的皮下给药，并降低了由于细胞因子峰值导致的毒性可能性。临床前癌症研究表明，基于IL - 15异二聚体的免疫疗法通过有利于细胞毒性细胞而非调节性细胞，促进了抗肿瘤反应的发展。