Dual Targeting of Innate and Adaptive Checkpoints on Tumor Cells Limits Immune Evasion

Xiaojuan Liu, Longchao Liu, Zhenhua Ren, Kaiting Yang, Hairong Xu, Yan Luan, Kai Fu, Jingya Guo, Hua Peng, Mingzhao Zhu, Yang Xin Fu

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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-SIRPα 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. CD47 and PD-L1 serve as critical innate and adaptive checkpoints, respectively. Liu et al. show CD47 and PD-L1 coordinate in tumor cells to evade immune response. Furthermore, a bispecific antibody design enables better targeting on tumor cells, but less on non-tumor cells, and enhanced therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)2101-2111
Number of pages11
JournalCell Reports
Volume24
Issue number8
DOIs
StatePublished - Aug 21 2018

Keywords

  • anti-PD-L1-SIRPα
  • anti-tumor immunotherapy
  • bispecific antibody
  • chemotherapy
  • dendritic cell
  • PD-L1
  • SIRPα
  • tumor evasion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Dual Targeting of Innate and Adaptive Checkpoints on Tumor Cells Limits Immune Evasion'. Together they form a unique fingerprint.

  • Cite this

    Liu, X., Liu, L., Ren, Z., Yang, K., Xu, H., Luan, Y., Fu, K., Guo, J., Peng, H., Zhu, M., & Fu, Y. X. (2018). Dual Targeting of Innate and Adaptive Checkpoints on Tumor Cells Limits Immune Evasion. Cell Reports, 24(8), 2101-2111. https://doi.org/10.1016/j.celrep.2018.07.062