Research Article: Engineering with EP2/EP4 knockout and IL-15 transpresentation renders stem cell-derived NK cells self-persistent and resistant to PGE2 inhibition
Abstract:
Adoptive Natural Killer (NK) cell transfer is a promising therapy for the treatment of cancer. We developed a GMP-compliant protocol to generate NK cells from hematopoietic stem and progenitor cells (HSPC-NK). However, the immunosuppressive tumor microenvironment — especially prostaglandin E2 (PGE2) signaling via E-prostanoid receptors EP2 and EP4— and lack of persistence of allogeneic NK cells hinders HSPC-NK therapeutic efficacy. Here, we enhanced the therapeutic efficacy of HSPC-NK cells by interfering with both EP2 and EP4 with antagonists or CRISPR-KO, and through engineering with IL-15 tethered to membrane-bound IL-15R? (tIL15). We found that CRISPR interference of EP2 and EP4 fully rescued proliferation and potency of HSPC-NK cells under PGE2 rich conditions. In addition, combined EP2/EP4 KO and tIL15 engineering renders HSPC-NK cells resistant to PGE2, while improving their survival and functionality against different tumor targets in cytokine-deprived environments. Altogether, our EP2/EP4-KO tIL15-HSPC-NK cells pose a promising therapy for cancer.
Introduction:
Natural Killer (NK) cells inherently recognize and elicit cytotoxic responses against tumor-transformed cells through a balance of inhibitory and activating receptors. Given their natural anti-tumor potential and their suitability for allogeneic use, adoptive transfer of NK cells has become an alternative attractive therapy for cancer treatment ( 1 ). In fact, many clinical trials have positively associated high NK cell frequencies with improved survival in both hematological and solid malignancies ( 2 – 4 ),…
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