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

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 establish...

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Bibliographic Details
Published in:Science immunology 2021-07, Vol.6 (61)
Main Authors: Wei, Yao, Ren, Xiaoxin, Galbo, Jr, Phillip M, Moerdler, Scott, Wang, Hao, Sica, R Alejandro, Etemad-Gilbertson, Bijan, Shi, Lei, Zhu, Liqiang, Tang, Xudong, Lin, Qi, Peng, Mou, Guan, Fangxia, Zheng, Deyou, Chinai, Jordan M, Zang, Xingxing
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
CD8-Positive T-Lymphocytes - immunology
Cell Survival
Cells, Cultured
Humans
Immune Tolerance
Immunoglobulins - genetics
Immunoglobulins - immunology
Killer Cells, Natural - immunology
Mice
Mice, Inbred BALB C
Neoplasms - drug therapy
Neoplasms - immunology
Receptors, KIR - antagonists & inhibitors
Receptors, KIR - immunology
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Summary: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 CD56 NK and terminally differentiated effector memory CD8 T (CD8 T ) cells. KIR3DL3 CD8 T 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.
ISSN:2470-9468
2470-9468
DOI:10.1126/sciimmunol.abf9792