Based on their observations in genetic knockouts that tumors evade both the the innate and adaptive immune system via expression of CD47 (a “don’t eat me” signal) and PD-L1, Liu and Liu et al. created a bispecific anti-PD-L1-SIRPα fusion protein, which preferentially targeted tumor cells, reduced tumor growth, and prolonged survival in a manner dependent on intratumoral CD8+ T cells, IFNα, and dendritic cell-specific cGAS/STING signaling. Combination of anti-PD-L1-SIRPα and doxorubicin (which upregulated calreticulin, an “eat me” signal, on tumor cells) synergized to enhance the antitumor effect.

CD47 on tumor cells protects from phagocytosis, while PD-L1 dampens T cell-mediated tumor killing. However, whether and how CD47 and PD-L1 coordinate is poorly understood. We reveal that CD47 and PD-L1 on tumor cells coordinately suppress innate and adaptive sensing to evade immune control. Targeted blockade of both CD47 and PD-L1 on tumor cells with a bispecific anti-PD-L1-SIRPalpha showed significantly enhanced tumor targeting and therapeutic efficacy versus monotherapy. Mechanistically, systemic delivery of the dual-targeting heterodimer significantly increased DNA sensing, DC cross-presentation, and anti-tumor T cell response. In addition, chemotherapy that increases "eat me" signaling further synergizes with the bispecific reagent for better tumor control. Our data indicate that tumor cells evolve to utilize both innate and adaptive checkpoints to evade anti-tumor immune responses and that tumor cell-specific dual-targeting of both checkpoints represents an improved strategy for tumor immunotherapy.

Author Info: (1) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

Author Info: (1) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (2) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. (3) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. (4) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. (5) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. (6) DingFu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (7) DingFu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (8) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. (9) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. (10) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhumz@ibp.ac.cn. (11) Chinese Academy of Sciences Key Laboratory of Infection and Immunity, IBP-UTSW Joint Immunotherapy Group, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Electronic address: yang-xin.fu@utsouthwestern.edu.

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