人源内源性逆转录病毒H长末端重复序列-结合蛋白2（HHLA2或B7-H7）是新发现的B7家族成员。HHLA2在实体瘤中异常表达，并根据与对应受体的相互作用发挥共刺激或共抑制活性。HHLA2与跨膜和免疫球蛋白结构域含2（TMIGD2，也称为CD28H）相互作用时具有共刺激效应，但与杀伤性细胞免疫球蛋白类受体、三个免疫球蛋白结构域和长胞浆尾巴3（KIR3DL3）相互作用时表现为共抑制效应。TMIGD2主要表达在静息或原始T细胞上，而KIR3DL3的表达则发生在激活的T细胞上。HHLA2 / KIR3DL3减弱了先天和适应性抗肿瘤免疫的反应，该轴的活动被认为是癌症患者弱预后的生物标志物。 HHLA2 / KIR3DL3促进CD8 + T细胞耗竭，并引起巨噬细胞定向向亲瘤M2表型。HHLA2在肿瘤和基质中表现出不同的表达谱和活性。肿瘤表达的HHLA2比编程死亡配体1（PD-L1）高，HHLA2与PD-L1的共表达表明了更严重的结果。在HHLA2高癌症患者中，建议的策略是使用单克隆抗体特异性抑制HHLA2抑制性受体KIR3DL3，而不是HHLA2配体。TMIGD2可以成为开发拮抗双特异性抗体的靶点，以阻碍肿瘤对程序性死亡-1（PD-1）/ PD-L1阻断疗法的抵抗。版权所有©2023年该出版物的作者。 Elsevier Masson SAS发表。保留所有权利。

Human endogenous retrovirus H long terminal repeat-associating protein 2 (HHLA2 or B7-H7) is a newly discovered B7 family member. HHLA2 is aberrantly expressed in solid tumors and exerts co-stimulatory or co-inhibitory activities dependent on interaction with counter receptors. HHLA2 represents co-stimulatory effects upon interaction with transmembrane and immunoglobulin domain containing 2 (TMIGD2, also called CD28H), but its interaction with killer cell Ig-like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) renders co-inhibitory effects. TMIGD2 is mainly expressed on resting or naïve T cells, whereas expression of KIR3DL3 occurs on activated T cells. HHLA2/KIR3DL3 attenuates responses from both innate and adaptive anti-tumor immunity, and the activity within this axis is regarded as a biomarker of weak prognosis in cancer patients. HHLA2/KIR3DL3 promotes CD8+ T cell exhaustion and induces macrophage polarity toward pro-tumor M2 phenotype. HHLA2 represents diverse expression profile and activity in tumor and stroma. Tumoral expression of HHLA2 is presumably higher compared with programmed death-ligand 1 (PD-L1), and HHLA2 co-expression with PD-L1 is indicative of more severe outcomes. A suggested strategy in patients with HHLA2high cancer is to use monoclonal antibodies for specifically suppressing the HHLA2 inhibitory receptor KIR3DL3, not the HHLA2 ligand. TMIGD2 can be a target for development of agonistic bispecific antibodies for hampering tumor resistance to the programmed death-1 (PD-1)/PD-L1 blockade therapy.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.