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.

The KIR repertoire of a West African chimpanzee population is characterized by limited gene, allele, and haplotype variation

“…Recently, the poliovirus receptor (PVR or CD155), which is highly expressed on tumors, has been described to interact with KIR2DL5. In this context, KIR2DL5 may induce NK cell suppression and facilitate tumor immune evasion ( 53 , 54 ). Additionally, PVR/CD155 appears to play a role in NK cell immunity in HIV-1 infection ( 55 ), in which downregulation of the receptor on infected CD4 + target T cells, a process mediated by the viral Nef protein, leads to increased antiviral activity among KIR2DL5-positive NK cells.…”

Killer cell immunoglobulin-like receptor (KIR) genes and their HLA ligands in a Brazilian population

“…KIR2DL5 may be related to potent human NK cell-mediated antitumor immunity immunosuppressive pathways, highlighting the great importance of knowing the repertoire of KIR genes and their HLA ligands in different populations. 35 Concerning activating genes, great variations were observed in all the studied populations. Compared to the Brazilian population, the KIR2DS1 gene was less common in southeastern Africa (p = 0.0001), KIR2DS2 and KIR2DS3 were less frequent in the Chinese (p = 0.0001; p = 0.0001, respectively) and Mexican populations (p = 0.04; p = 0.006, respectively) and KIR2DS3 was more common in individuals of southeastern Africa (p = 0.0001).…”

TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors

“…A recombinant protein composed of the IgV domain of human B7-H3 fused to a human Fc fragment was generated in an inducible secreted serum-free Drosophila expression system as described previously ( 64 ) and then used for mice immunization. After immunization, hybridomas were generated by fusing NSO myeloma cells and mouse splenocytes using the standard methods as previously described ( 19 ).…”