Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses—the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)—to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.

溶瘤病毒 (OV) 可以引发深刻的先天性和适应性免疫反应，有可能增强和降低 OV 的活性。自然杀伤（NK）细胞可以介导有效的抗病毒和抗肿瘤反应，但没有关于 NK 细胞在溶瘤腺病毒活性中的作用的数据。在这里，我们使用了两种不同的溶瘤腺病毒——Ad5 E1A CR2 缺失突变体dl 922-947（C 组）和嵌合 Ad3/Ad11p 突变体 enadenotucirev（B 组）——来研究 NK 细胞对整体抗癌的影响对卵巢癌的疗效。由于人类腺病毒不能在小鼠细胞中复制，因此我们利用了来自外周血和卵巢癌腹水的原代人类 NK 细胞。我们的结果表明， dl 922-947 和 enadenotucirev 不会感染 NK 细胞，但会诱导针对腺病毒感染的卵巢癌细胞的接触依赖性激活和抗癌细胞毒性。此外，操作 NK 受体 DNAM-1（DNAX 辅助分子-1）和 TIGIT（具有 Ig 和 ITIM 结构域的 T 细胞免疫受体）可显着影响 NK 对腺病毒感染细胞的细胞毒性。总之，这些结果表明 NK 细胞可以增加卵巢癌中溶瘤腺病毒的活性，并表明通过阻断抑制性 NK 受体 TIGIT 进一步增强 NK 活性的策略可以增强 OV 的治疗潜力。