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^dim NK and terminally differentiated effector memory CD8⁺ T (CD8⁺ T_EMRA) cells. KIR3DL3⁺ CD8⁺ T_EMRA 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.

B7 家族配体 HERV-H LTR 相关蛋白 2 (HHLA2) 是癌症免疫治疗的一个有吸引力的靶点，因为它具有共抑制功能、在人类癌症中过度表达以及与不良预后相关。然而，对 HHLA2 通路的了解并不完整。 HHLA2 具有已确定的阳性受体跨膜和免疫球蛋白 (Ig) 结构域，包含 2 (TMIGD2)，但其阴性受体人杀伤细胞 Ig 样受体、三个 Ig 结构域和长胞质尾 (KIR3DL3) 特征尚未明确。在这里，KIR3DL3 和 TMIGD2 同时结合到 HHLA2 的不同位点。 KIR3DL3主要在^CD56dimNK和终末分化效应记忆CD8 ⁺ T(CD8 ⁺ _TEMRA )细胞上表达。 KIR3DL3 ⁺ CD8 ⁺ T _EMRA获得了 NK 样表型和功能。 HHLA2 的参与将 KIR3DL3 招募到免疫突触，并共同抑制 CD8 ⁺ T 和 NK 细胞的功能和杀伤，诱导免疫逃避的 HHLA2 ⁺肿瘤。 KIR3DL3 招募 SHP-1 和 SHP-2 来减弱 Vav1、ERK1/2、AKT 和 NF-κB 信号传导。来自人肾、肺、胆囊和胃的 HHLA2 ⁺肿瘤被 KIR3DL3 ⁺免疫细胞浸润。 KIR3DL3 阻断可抑制多种人源化小鼠模型中的肿瘤生长。因此，我们的研究结果阐明了 KIR3DL3 抑制功能的分子和细胞基础，证明 KIR3DL3-HHLA2 途径是癌症的潜在免疫治疗靶点。