Wei and Ren et al. demonstrated that KIR3DL3, a human killer cell Ig-like receptor family member, is predominantly expressed in CD8+ TEMRA and CD56dimCD16+ NK cells. Interaction with one known ligand, HHLA2, in tumor cells suppressed the function of KIR3DL3+ immune cells leading to immune evasion. KIR3DL3-mediated NK cell suppression required the inhibitory ITIM domain, which recruited SHP-1/2 to inhibit downstream Vav1, ERK1/2, AKT, and NF-κB signaling. KIR3DL3+ immune cells infiltrated multiple HHLA2+ cancers, and KIR3DL3 blockade reinvigorated the effector functions of NK cells and promoted antitumor immunity.
Contributed by Shishir Pant
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.