Journal
EMBO MOLECULAR MEDICINE
Volume -, Issue -, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202317804
Keywords
HLA-E; intratumoral immunotherapy; NK; NKG2A; Qa-1(b)
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NK cell reactivity against cancer is suppressed in the tumor microenvironment through the interaction of the inhibitory receptor NKG2A with non-classical MHC-I molecules. Injection of anti-NKG2A and anti-Qa-1(b) antibodies enhances the therapeutic effects of NK cells and shows partial efficacy against distant tumors. In experiments with human cancer cells expressing HLA-E, injection of activated allogeneic human NK cells and anti-NKG2A antibodies synergistically achieve therapeutic effects.
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.
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