NK 细胞上 NKG2D 配体表达诱导 NKG2D 介导的细胞因子信号交叉耐受并降低 NK 细胞抗肿瘤免疫

Studies support a role for natural killer (NK) cells in cancer control, making these cells attractive for immunotherapy. One method being tested to make effective NK cells is the ex vivo activation with interleukin (IL)-12, IL-15, and IL-18.

We demonstrate that this induces NKG2D ligands on NK cells. By engaging NKG2D, this NKG2D ligand expression eliminated the ability of both mouse and human NK cells to control tumor growth in vivo and in vitro, respectively. NKG2D-NKG2D ligand interaction between mouse NK cells reduced NK cell proliferation, CD25 and T-bet expression, and tumor necrosis factor and interferon release.

NKG2D signaling induced between human NK cells similarly decreased interferon but did not affect T-bet or CD25 expression. These data demonstrate that NKG2D signaling can cross-tolerize cytokine signaling and suggest that eliminating this signaling could be beneficial in NK cell adoptive therapy.

Further, these results highlight a need to better delineate effects downstream of NKG2D signaling in human, rather than mouse, NK cells.