Wang et al. generated αTIGIT-IL2, an immunocytokine comprising IL-2 and an anti-TIGIT scFv fused to a human IgG1Fc. Within tumors, αTIGIT-IL2 (delivered i.p.) preferentially bound to Tregs (due to their high CD25 expression), reduced Treg inhibitory activity, and stimulated Treg production of IFNγ to promote a “hot” TME. The enhanced inflammatory environment of the TME recruited and activated neutrophils to be proinflammatory and act as APCs to boost CD8+ T cell antitumor activity in multiple “cold” murine tumor models. αTIGIT-IL2 and a blocking PD-1 Ab synergized to inhibit ICB-resistant TNBC tumor growth and induce immune memory.
Contributed by Paula Hochman
ABSTRACT: Administration of IL-2 may promote the suppressive function and proliferation of Treg cells that cause immune tolerance in patients with cancer, which causes low-dose IL-2 to fail in achieving an optimal anti-tumor effect. Here, we designed an immunocytokine by fusing IL-2 and an anti-TIGIT monoclonal antibody, named αTIGIT-IL2, that targets Treg cells and promotes their fragility in the tumor milieu. These fragile-like Treg cells show impaired suppressive function and high IFN-γ production, triggering an immune-reactive tumor microenvironment. Such inflammation leads to the recruitment and functional reprogramming of intratumoral neutrophils, improving cross-talk between neutrophils and CD8+ T cells and enhancing the antitumor ability of CD8+ T cells. Combination therapy with αTIGIT-IL2 and PD-1 blocker could eliminate triple-negative breast cancer (TNBC) tumors resistant to immune checkpoint blockade (ICB) therapy. These findings provide the basis for developing a new generation of immunocytokines that target Treg cells and promote their fragility in the tumor milieu, resulting in robust antitumor immunity.
Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Scie
Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (2) MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (3) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (4) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (5) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (6) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (7) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (8) Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (9) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Hefei TG ImmunoPharma Corporation Limited, Hefei, China. (10) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. mahongdi@ustc.edu.cn. (11) Hefei TG ImmunoPharma Corporation Limited, Hefei, China. haoyusun@ustc.edu.cn. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China. haoyusun@ustc.edu.cn. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. haoyusun@ustc.edu.cn. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. haoyusun@ustc.edu.cn. (12) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. tzg@ustc.edu.cn. Hefei TG ImmunoPharma Corporation Limited, Hefei, China. tzg@ustc.edu.cn. Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. tzg@ustc.edu.cn. (13) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. ustczxh@ustc.edu.cn. Hefei TG ImmunoPharma Corporation Limited, Hefei, China. ustczxh@ustc.edu.cn. Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. ustczxh@ustc.edu.cn.
