Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity
Xiaoxin Ren, … , Deyou Zheng, Xingxing Zang
Xiaoxin Ren, … , Deyou Zheng, Xingxing Zang
Published November 15, 2022
Citation Information: J Clin Invest. 2022;132(22):e163620. https://doi.org/10.1172/JCI163620.
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Research Article Immunology Oncology

Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity

Abstract

Cancer immunotherapy targeting the TIGIT/PVR pathway is currently facing challenges. KIR2DL5, a member of the human killer cell, immunoglobulin-like receptor (KIR) family, has recently been identified as another binding partner for PVR. The biology and therapeutic potential of the KIR2DL5/PVR pathway are largely unknown. Here we report that KIR2DL5 was predominantly expressed on human NK cells with mature phenotype and cytolytic function and that it bound to PVR without competition with the other 3 known PVR receptors. The interaction between KIR2DL5 on NK cells and PVR on target cells induced inhibitory synapse formation, whereas new monoclonal antibodies blocking the KIR2DL5-PVR interaction robustly augmented the NK cytotoxicity against PVR+ human tumors. Mechanistically, both intracellular ITIM and ITSM of KIR2DL5 underwent tyrosine phosphorylation after engagement, which was essential for KIR2DL5-mediated NK suppression by recruiting SHP-1 and/or SHP-2. Subsequently, ITIM/SHP-1/SHP-2 and ITSM/SHP-1 downregulated the downstream Vav1/ERK1/2/p90RSK/NF-κB signaling. KIR2DL5+ immune cells infiltrated in various types of PVR+ human cancers. Markedly, the KIR2DL5 blockade reduced tumor growth and improved overall survival across multiple NK cell–based humanized tumor models. Thus, our results revealed functional mechanisms of KIR2DL5-mediated NK cell immune evasion, demonstrated blockade of the KIR2DL5/PVR axis as a therapy for human cancers, and provided an underlying mechanism for the clinical failure of anti-TIGIT therapies.

Authors

Xiaoxin Ren, Mou Peng, Peng Xing, Yao Wei, Phillip M. Galbo Jr., Devin Corrigan, Hao Wang, Yingzhen Su, Xiaoshen Dong, Qizhe Sun, Yixian Li, Xiaoyu Zhang, Winfried Edelmann, Deyou Zheng, Xingxing Zang

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Figure 4

KIR2DL5 inhibited NK cell function and mediated PVR+ tumor immune resistance.

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KIR2DL5 inhibited NK cell function and mediated PVR+ tumor immune resist...
(A–C) Redirected cytotoxicity of KIR2DL5+ primary NK cells against P815. (A) The lysis of P815 cells (n = 4). (B) The degranulation (CD107a) and cytokine production (IFN-γ and TNF-γ) of KIR2DL5+ primary NK cells (n = 4). CD56 served as negative control. (C) Cytokine production in the coculture supernatant of KIR2DL5+ primary NK cells with the indicated antibody-coated P815 (n = 5). Data are represented as mean ± SEM. (D) Lysis of scrambled control or PVRKO A427 or Jurkat cells by KIR2DL5-transduced primary NK cells (KIR2DL5/NK) or KIR2DL5– control NK cells (Control NK) at indicated E/T ratios. (E) PVR-KIR2DL5–mediated inhibitory synapse formation. Left: Representative imaging of cell conjugates acquired upon sorted KIR2DL5+ primary NK contact with control-YFP/Raji (top) or PVR-YFP/Raji (bottom), followed by staining with anti-KIR2DL5 mAbs and phalloidin. Scale bars: 10 μm. Right: Intensity quantification of F-actin, YFP, and KIR2DL5 at the immunological synapses (IS) and the cell surface away from synapses (Non-IS) from KIR2DL5+ NK cell–Control Raji (n = 25) and KIR2DL5+ NK-PVR/Raji (n = 35) conjugates. (F) Lysis of scrambled control or PVRKO A427 (top) or Jurkat (bottom) cells by sorted KIR2DL5+ primary NK cells in the presence of F8B30 or mIgG1 at indicated E/T ratios. In D and F, data are mean for duplicate measurements and representative of 3 independent experiments with 3 different donors. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by 1-way ANOVA (A and B), 2-tailed paired Student’s t test (C and E), or multiple unpaired t test (D and F).