NKG2D Ligands in Cancer

NK cell transplantation has been increasingly used to treat cancers that are resistant to chemotherapy. However, not all cancers are susceptible to NK cell killing. The prevalence and mechanisms of NK cell resistance have not been well elucidated. Because NKG2D is a major activating receptor on NK cells, we sought to test the hypothesis that NKG2D is the primary pathway in tumor cell recognition. Herein, we comprehensively assessed 20 cancer cell lines representing a broad array of cancer types. In line with our primary hypothesis, no cancer cell lines that expressed low levels of NKG2D ligands were susceptible to NK cell lysis. Furthermore, we found that only 30% of the cancer cell lines were susceptible to NK cell killing and all of them expressed high level of NKG2D ligands. The dependency on NKG2D pathway in these NK susceptible cells was confirmed by anti-NKG2D antibody blocking experiments. For the 70% of cell lines that were resistant to NK cells, 65% were due to silencing of NKG2D ligand expression, whereas 35% were due to insufficient NKG2D activation. For the former cell lines, NKG2D ligand expression was found to be downregulated at the mRNA or protein level. By histone acetylation or proteasome modulation, these regulatory checkpoints could be circumvented to obtain sufficient surface expression of NKG2D ligands to overcome NK resistance. For the latter cancer cell lines that were NK resistant despite high NKG2D ligand expression, KIR inhibition was found to override NKG2D activation in 80% of these cancers. MHC blockade successfully increased NK susceptibility of these cell lines. In the remaining 20%, downregulation of ICAM-1 was responsible for NK resistance. In conclusion, we successfully obtained sufficient evidence to support our hypothesis that NKG2D is the primary pathway for tumor cell recognition. Evasion of the NKG2D pathway is common through NKG2D ligand silencing, KIR inhibition, or inadequate expression of adhesion molecules to mediate immune-synapse formation. Because these resistance mechanisms are readily amenable to therapeutic alteration, NK cell transplantation holds promise for future cancer therapy