PDF(Pubmed)
Abstract：
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-1b in mice. We found that intratumoral delivery of NK cells attains significant therapeutic effects only if co-injected with anti-NKG2A and anti-Qa-1b 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.
摘要：
可以想象，抑制性受体NKG2A与非经典MHC-I分子HLA-E或小鼠Qa-1b的相互作用在肿瘤微环境中抑制了NK细胞对癌症的反应性。我们发现，只有在与抗NKG2A和抗Qa-1b阻断性单克隆抗体共同注射针对实体小鼠肿瘤模型时，NK细胞的瘤内递送才能达到显着的治疗效果。这种治疗活性取决于内源性CD8T细胞和1型常规树突细胞(cDC1)。此外，与全身性抗PD-1mAb治疗联合治疗后,抗肿瘤作用得到增强,并对远处未注射的肿瘤取得部分外移疗效.在携带表达HLA-E的人类癌细胞的异种移植小鼠中，肿瘤内共注射活化的同种异体人NK细胞和临床级抗NKG2AmAb（monalizumab）协同实现了治疗效果。总之,这些研究为基于肿瘤内NK细胞的免疫治疗的临床潜力提供了证据,这些免疫治疗通过引发内源性T细胞反应而发挥抗肿瘤功效.
