NK-cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non-classical MHC-I molecules HLA-E in humans or Qa-1^b in mice. We found that intratumoral delivery of NK cells attains significant therapeutic effects only if co-injected with anti-NKG2A and anti-Qa-1^b blocking monoclonal antibodies against solid mouse tumor models. Such therapeutic activity was contingent on endogenous CD8 T cells and type-1 conventional dendritic cells (cDC1). Moreover, the anti-tumor effects were enhanced upon combination with systemic anti-PD-1 mAb treatment and achieved partial abscopal efficacy against distant non-injected tumors. In xenografted mice bearing HLA-E-expressing human cancer cells, intratumoral co-injection of activated allogeneic human NK cells and clinical-grade anti-NKG2A mAb (monalizumab) synergistically achieved therapeutic effects. In conclusion, these studies provide evidence for the clinical potential of intratumoral NK cell-based immunotherapies that exert their anti-tumor efficacy as a result of eliciting endogenous T-cell responses.

中文翻译：

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NK 细胞和 NKG2A 中和单克隆抗体瘤内共注射

可以想象，在肿瘤微环境中，抑制性受体 NKG2A 与人类的非经典 MHC-I 分子 HLA-E 或小鼠的Qa-1 ^b相互作用，可抑制 NK 细胞对癌症的反应。我们发现，只有在与抗实体小鼠肿瘤模型的抗 NKG2A 和抗 Qa-1 ^b阻断单克隆抗体共同注射时，NK 细胞的瘤内递送才能获得显着的治疗效果。这种治疗活性取决于内源性 CD8 T 细胞和 1 型常规树突状细胞 (cDC1)。此外，与全身性抗PD-1 mAb治疗相结合，抗肿瘤作用得到增强，并对远处非注射肿瘤实现了部分远隔疗效。在携带表达 HLA-E 的人类癌细胞的异种移植小鼠中，瘤内共注射活化的同种异体人类 NK 细胞和临床级抗 NKG2A 单克隆抗体（莫那珠单抗）可协同实现治疗效果。总之，这些研究为基于 NK 细胞的肿瘤内免疫疗法的临床潜力提供了证据，这种疗法通过引发内源性 T 细胞反应来发挥抗肿瘤功效。