8: Heterodimeric IL-15 promotes tumor control through the regulation of the balance of effector and regulatory cells via an IL-2 deprivation mechanism

8: Heterodimeric IL-15 promotes tumor control through the regulation of the balance of effector and regulatory cells via an IL-2 deprivation mechanism

Interleukin-15 (IL-15) is a common γ -chain cytokine that plays a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha chain that are together termed heterodimeric IL-15 (hetIL-15). HetIL-15 produced from engineered human cell lines showed favorable pharmacokinetics and bioactivity compared to monomeric IL-15 in both mice and macaques. We investigated the anti-tumor efficacy of hetIL-15, using the MC38 colon carcinoma mouse model. hetIL-15 resulted in a significant delay in tumor growth, when administered intraperitoneally every 2days for 2weeks. In addition, intratumoral delivery of hetIL-15 induced regression of established tumors and cured 50% of mice. Tumor-free mice were resistant to tumor challenge, demonstrating the development of specific anti-tumor immune responses. We further dissected the mechanism leading to tumor control in hetIL-15-treated mice, discovering a new interplay between IL-15 and the cognate cytokine interleukin-2 (IL-2). Repeated injections of hetIL-15 resulted in an increased CD8+/Treg cells ratio in spleen, lymph nodes and tumor microenvironment. Interestingly, hetIL-15 induced a transient accumulation of CD8+ T cells expressing the high affinity IL-2 receptor CD25, that compete with CD25+ Treg for the available IL-2. In addition, IL-15 decreased the frequency of IL-2-producing CD4+ T cells, while increasing their ability to secrete IFN γ . These data suggest that hetIL-15 treatment limits Treg fitness through a concerted action of both CD8+ and CD4+ T cells, that results in an IL-2 deprived environment. Preclinical cancer studies support the use of hetIL-15 in tumor immunotherapy approaches to promote the development of anti-tumor responses by favoring effector over regulatory cells.

白细胞介素 - 15（IL - 15）是一种常见的γ链细胞因子，在T细胞和NK细胞的活化与增殖中发挥重要作用，并且在对抗感染和癌症方面具有巨大潜力。我们先前已经表明，体内的生物活性IL - 15包含IL - 15链与可溶性或细胞相关的IL - 15受体α链的复合物，它们一起被称为异二聚体IL - 15（hetIL - 15）。从工程化人类细胞系产生的hetIL - 15在小鼠和猕猴中与单体IL - 15相比，显示出良好的药代动力学和生物活性。我们利用MC38结肠癌小鼠模型研究了hetIL - 15的抗肿瘤功效。当每2天腹腔注射一次，持续2周时，hetIL - 15导致肿瘤生长显著延迟。此外，瘤内注射hetIL - 15诱导已形成的肿瘤消退，并使50%的小鼠治愈。无瘤小鼠对肿瘤攻击具有抵抗力，这表明产生了特异性抗肿瘤免疫反应。我们进一步剖析了hetIL - 15治疗小鼠中导致肿瘤控制的机制，发现了IL - 15与同源细胞因子白细胞介素 - 2（IL - 2）之间的一种新的相互作用。重复注射hetIL - 15导致脾脏、淋巴结和肿瘤微环境中CD8⁺/Treg细胞比例增加。有趣的是，hetIL - 15诱导表达高亲和力IL - 2受体CD25的CD8⁺ T细胞的短暂积累，这些细胞与CD25⁺ Treg竞争可用的IL - 2。此外，IL - 15降低了产生IL - 2的CD4⁺ T细胞的频率，同时提高了它们分泌干扰素γ的能力。这些数据表明，hetIL - 15治疗通过CD8⁺和CD4⁺ T细胞的协同作用限制了Treg的适应性，从而导致一个IL - 2缺乏的环境。临床前癌症研究支持在肿瘤免疫治疗方法中使用hetIL - 15，通过使效应细胞优于调节细胞来促进抗肿瘤反应的发展。