Immunosuppressive IL-10 has anti-cancer efficacy but the mechanism is unclear. Qiao, Liu, and Dong et al. generated a long-lived, EGFR-targeted cetuximab/IL-10 fusion protein (CmAb-(IL-10)2), which had minimal toxicity and accumulated in EGFR+ tumors. In mouse models, CmAb-(IL-10)2 potently decreased tumor burden with immunological memory, prolonged survival, and decreased intratumoral CD8+ T cell apoptosis by suppressing production of IFNγ and IL-12 by dendritic cells. Significantly superior antitumor efficacy was obtained in combination with anti-CTLA-4 and anti-PD-L1, supporting future clinical opportunity.
Contributed by Katherine Turner
Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8(+) T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8(+) T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8(+) tumor-infiltrating lymphocyte apoptosis through regulating IFN-gamma production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8(+) T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.
Author Info: (1) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Jian.Qiao@UTSouthwestern.edu. (2) The Department of Pat
Author Info: (1) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Jian.Qiao@UTSouthwestern.edu. (2) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (3) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (4) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (5) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (6) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (7) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (8) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (9) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (10) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (11) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (12) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. Electronic address: tingxu@alphamab.com. (13) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Yang-Xin.Fu@UTSouthwestern.edu.
