NKG2D engagement on human NK cells leads to DNAM‐1 hypo‐responsiveness through different converging mechanisms

Natural killer (NK) cell activation is regulated by activating and inhibitory receptors that facilitate diseased cell recognition. Among activating receptors, NKG2D and DNAM‐1 play a pivotal role in anticancer immune responses since they bind ligands upregulated on transformed cells. During tumor progression, however, these receptors are frequently downmodulated and rendered functionally inactive. Of note, NKG2D internalization has been associated with the acquisition of a dysfunctional phenotype characterized by the cross‐tolerization of unrelated activating receptors. However, our knowledge of the consequences of NKG2D engagement is still incomplete. Here, by cytotoxicity assays combined with confocal microscopy, we demonstrate that NKG2D engagement on human NK cells impairs DNAM‐1‐mediated killing through two different converging mechanisms: by the upregulation of the checkpoint inhibitory receptor TIGIT, that in turn suppresses DNAM‐1‐mediated cytotoxic function, and by direct inhibition of DNAM‐1‐promoted signaling. Our results highlight a novel interplay between NKG2D and DNAM‐1/TIGIT receptors that may facilitate neoplastic cell evasion from NK cell‐mediated clearance. During tumor progression, NKG2D stimulation renders NK cell defective in their ability to lyse PVR‐expressing target cells through direct inhibition of DNAM‐1‐ mediated signals and upregulating the inhibitory receptor TIGIT. Our results highlight a novel interplay between NKG2D and DNAM‐1/TIGIT that may facilitate transformed cell evasion from NK cell recognition.