KIR3DL3-HHLA2 is a human immunosuppressive pathway and a therapeutic target

Abstract

The B7 family ligand HERV-H LTR–associating protein 2 (HHLA2) is an attractive target for cancer immunotherapy because of its coinhibitory function, overexpression in human cancers, and association with poor prognoses. However, the knowledge of the HHLA2 pathway is incomplete. HHLA2 has an established positive receptor transmembrane and immunoglobulin (Ig) domain containing 2 (TMIGD2) but a poorly characterized negative receptor human killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3). Here, KIR3DL3 and TMIGD2 simultaneously bound to different sites of HHLA2. KIR3DL3 was mainly expressed on CD56dim NK and terminally differentiated effector memory CD8+ T (CD8+ TEMRA) cells. KIR3DL3+ CD8+ TEMRA acquired an NK-like phenotype and function. HHLA2 engagement recruited KIR3DL3 to the immunological synapse and coinhibited CD8+ T and NK cell function and killing, inducing immune-evasive HHLA2+ tumors. KIR3DL3 recruited SHP-1 and SHP-2 to attenuate Vav1, ERK1/2, AKT, and NF-κB signaling. HHLA2+ tumors from human kidney, lung, gallbladder, and stomach were infiltrated by KIR3DL3+ immune cells. KIR3DL3 blockade inhibited tumor growth in multiple humanized mouse models. Thus, our findings elucidated the molecular and cellular basis for the inhibitory function of KIR3DL3, demonstrating that the KIR3DL3-HHLA2 pathway is a potential immunotherapeutic target for cancer.

Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 Possesses Prognostic Significance and Promotes Progression of Papillary Thyroid Cancer

“…15 , 25–27 Therefore, immune-related processes should attract special attention, which might be a potential mechanism that mediates the tumor promoter role of HHLA2 in PTC. 10 , 26 Further mechanism investigations that would leak out the signaling and receptors of HHLA2 are warranted, which would be a part of the future studies.…”

“…24 Moreover, the role of HHLA2 in immune regulation also implies the potential of HHLA2 in immunotherapeutic approaches as well as in the therapy of PTC. 15,[25][26][27] Therefore, immune-related processes should attract special attention, which might be a potential mechanism that mediates the tumor promoter role of HHLA2 in PTC. 10,26 Further mechanism investigations that would leak out the signaling and receptors of HHLA2 are warranted, which would be a part of the future studies.…”

Human endogenous retrovirus-H long terminal repeat-associating 2: The next immune checkpoint for antitumour therapy

“…separately and simultaneously identified that KIR3DL3 was an inhibitory receptor of HHLA2 and KIR3DL3-HHLA2 axis was an immunosuppressive pathway in cancer immunity, making HHLA2-related studies step into a new chapter. 7 , 8 …”

“…Recently, studies on a promising immune checkpoint, Human endogenous retrovirus-H long terminal repeat-associating 2 (HHLA2), are flourishing because its co-inhibitory receptor, killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3), is newly identified. 7 , 8 This makes HHLA2-KIR3DL3 pathway a novel potential target for cancer immunotherapy. HHLA2, also known as B7-H7/B7y, is a type Ι transmembrane protein that belongs to B7 family.…”

“…independently discovered KIR3DL3 as a co-inhibitory receptor of HHLA2 did scientists eventually complement the research gap of HHLA2-involved immunosuppressive pathway. 7 , 8 Therefore, in this review, we summarize the expression profile and clinical features of HHLA2 based on current literatures, and discuss the dual immunological roles of HHLA2 in human cancer development, highlighting that precise immunotherapeutic targeting of HHLA2 and its receptors may provide promising strategies for malignancy treatment.…”