The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer

Affiliations

• Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
• Institute of Materials Science and Engineering, EPFL, Lausanne, Switzerland
• Department of Biomedical Engineering, Yale University, New Haven, CT, USA
• Institute of Chemical Sciences and Engineering, EPFL, Lausanne, Switzerland
• Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
• Department of Oncology, University of Lausanne, Epalinges, Switzerland
• Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
• State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China
• Jinhua Institute of Zhejiang University, Jinhua, China

PMID:  #  DOI: 10.1038/s41586-024-07962-4

Abstract

Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. Here we show that an interleukin-4 fusion protein (Fc–IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc–IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc–IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8+ TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc–IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc–IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.

当前癌症免疫治疗主要集中在诱导抗癌的1型免疫反应，但长期完全缓解仍然不常见。一个关键问题是，是否可以在以1型为中心的免疫治疗中协调2型免疫，以实现对癌症的持久反应。我们展示了白细胞介素-4融合蛋白（Fc–IL-4），一种典型的2型细胞因子，直接作用于CD8+ T细胞，丰富了肿瘤内功能性终末疲惫CD8+ T细胞。因此，Fc–IL-4增强了以1型免疫为中心的过继T细胞转移或免疫检查点抑制疗法的抗肿瘤效果，并在多个同种异体和异种移植肿瘤模型中诱导了持久缓解。在机制上，我们发现Fc–IL-4通过信号转导和转录激活因子6（STAT6）和哺乳动物雷帕霉素靶蛋白（mTOR）通路发信号，提高了CD8+ T细胞的糖酵解代谢和烟酰胺腺嘌呤二核苷酸（NAD）浓度，依赖于乳酸脱氢酶A。Fc–IL-4介导的代谢调节对于重振肿瘤内CD8+ T细胞是不可或缺的。这些发现强调了Fc–IL-4作为一种有效的2型细胞因子基础的免疫治疗，与1型免疫协同作用，以诱发对癌症的持久反应。我们的研究不仅揭示了这两种免疫反应之间的协同作用，还提出了一种创新策略，通过整合2型免疫因子推动下一代癌症免疫治疗的发展。