The nuclear factor‐κB pathway down‐regulates expression of the NKG 2D ligand H60a in vitro : implications for use of nuclear factor‐κB inhibitors in cancer therapy

Summary NKG 2D ligands are cell surface proteins that activate NKG 2D, a receptor used by natural killer ( NK ) cells to detect virus‐infected and transformed cells. When tumour cells express high levels of NKG 2D ligands, they are rejected by the immune system. Hence, reagents that increase NKG 2D ligand expression on tumour cells can be important for tumour immunotherapy. To identify genes that regulate the NKG 2D ligand H60a, we performed a microarray analysis of 3′‐methylcholanthrene‐induced sarcoma cell lines expressing high versus low H60a levels. A20, an inhibitor of nuclear factor‐κB ( NF ‐κB) activation, was differentially expressed in H60a‐hi sarcoma cells. Correspondingly, treatment of tumour cells with inhibitors of NF ‐κB activation, such as sulfasalazine (slz), BAY ‐11‐7085, or a non‐phosphorylatable IκB, led to increased levels of H60a protein, whereas transduction of cells with an active form of IκB kinase‐β ( IKK β) led to decreased levels of H60a. The regulation probably occurred at the transcriptional level, because NF ‐κB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumour cells with slz enhanced their killing by NK cells in vitro , suggesting that NF ‐κB inhibition can lead to tumour cell rejection. Indeed, when we blocked the NF ‐κB pathway specifically in tumour cells, there was decreased tumour growth in wild‐type but not immune‐deficient mice. Our results suggest that reagents that can block NF ‐κB activity specifically in the tumour and not the host immune cells would be efficacious for tumour therapy.