Engineering NK-92 Cell by Upregulating CXCR2 and IL-2 Via CRISPR-Cas9 Improves Its Antitumor Effects as Cellular Immunotherapy for Human Colon Cancer

Abstract

Natural killer (NK) cells have shown good application prospects in adoptive cellular immunotherapy against cancer. However, due to its insufficient infiltration and low activity, the therapeutic effect of infused NK cells has been limited in solid tumors, such as colorectal cancer. It has been proved that tumor-produced chemokines regulate the migration of NK cells expressing corresponding chemokine receptors, and cytokines could enhance the antitumor activity of NK cells. In this study, we innovatively upregulated the expression of chemokine receptor CXC chemokine receptor 2 (CXCR2) and cytokine interleukin (IL)-2 on NK-92 cells using CRISPR-Cas9 gene-editing technology. We demonstrated that overexpressing CXCR2 and IL-2 promotes NK-92 cells to increasingly transfer into tumor sites and achieve stronger cell-killing and proliferation activity. Moreover, the inhibitory effects of gene-edited NK-92 cells on the growth of human colon cancer <i>in vivo</i> were also improved. The tumor burden of tumor-bearing mice was reduced, and their survival time was significantly prolonged. Gene-editing modification NK cells are expected to become a novel and promising tumor treatment strategy.