CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1

Abstract

SignificanceCD226 is an important activating receptor involved in mediating natural killer (NK) cell responses against tumors, but how CD226 exerts control over NK cell function is not fully understood. CD226 belongs to the poliovirus receptor (PVR)-nectin family that includes TIGIT and CD96, with TIGIT garnering much attention as a key checkpoint in T cell and NK cell antitumor responses and as an immunotherapy target. Thus, it is imperative to determine how CD226 counteracts the actions of TIGIT and CD96 with which it competes for binding to its ligands such as CD155 (PVR). We demonstrate that CD226 engagement of CD155 is required for phosphorylation of transcription factor FOXO1, resulting in inactivation of its negative regulatory control over NK cell effector function.

CD96 functions as a co‐stimulatory receptor to enhance CD8+ T cell activation and effector responses

“…3B). CD155 and/or CD112 are ligands for CD96, so to demonstrate specificity of CD96‐mediated killing, B16F10 target cells devoid of CD155/CD112 expression (B16.DKO [11]) were included. WT OT‐I killing was dramatically reduced if target cells did not express CD155/CD112.…”

“…CD96, T cell Ig and ITIM domain (TIGIT) and CD226 all share a common ligand, CD155 (poliovirus receptor, PVR), and belong to the PVR‐nectin family [2,3]. TIGIT has inhibitory function on both T cells and NK cells [4–7], whereas CD226 is an activating receptor that mediates cytotoxicity against tumor cells by NK cells and CD8 + T cells, particularly in the absence of other co‐stimulatory molecules [8–11]. The co‐inhibitory/co‐stimulatory relationship between TIGIT and CD226 is reminiscent of CTLA‐4/CD28, and the kinetics of TIGIT/CD226 expression are also similar to CTLA‐4/CD28, where the co‐stimulatory receptor is expressed on naïve and resting T cells while the co‐inhibitory receptor is induced upon T cell activation [2,3].…”

Overexpression of an Immune Checkpoint (CD155) in Breast Cancer Associated with Prognostic Significance and Exhausted Tumor-Infiltrating Lymphocytes: A Cohort Study

“…The interaction increased NK-mediated suppression of melanoma metastasis [36]. CD155 mediated NK cell cytotoxicity through the AKT-FOXO1 pathway [37]. The immune regulatory role of CD155 might depend on the circumstances in the tumor microenvironment.…”

Deficiency of platelet adhesion molecule CD226 causes megakaryocyte development and platelet hyperactivity

“…It has been well‐documented that in CD226 associated with integrin lymphocyte function‐associated antigen 1 (LFA‐1) (CD11a/CD18, α L β 2 ), ligation of CD226, and LFA‐1 with their respective ligands triggers the cytokine secretion and cytotoxicity by T and natural killer (NK) cells 5 . The ligands for CD226 are CD112 (nectin‐2) and CD155 (poliovirus receptor), which are broadly expressed on normal endothelial, epithelial, fibroblastic cells, and tumor cells such as melanomas and carcinomas 5‐7 . CD226 plays synergistic roles in the following three molecules: T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibition motif domain (TIGIT), class I restricted T‐cell‐associated molecule, and CD96 (also known as T‐cell activation increased late expression) 8 .…”

“…CD226 plays synergistic roles in the following three molecules: T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibition motif domain (TIGIT), class I restricted T‐cell‐associated molecule, and CD96 (also known as T‐cell activation increased late expression) 8 . Thus, CD226 is a potential target in NK cell‐mediated immunotherapy against tumors 7 …”