NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer

SIMPLE SUMMARY: NKG2D is a type of immune receptor that is expressed on several subsets of lymphocytes and involved in the recognition and elimination of infected cells and cancer cells. The discovery of NKG2D as a therapeutic target for cancer has led to the development of novel immunotherapy strategies that aim to activate the immune system to fight various types of cancer. Our study explores the role played by NKG2D in colorectal cancer. We show that high expression of NKG2D is associated with decreased survival in a subset of patients, in contrast with the protective role observed in other cancer types. Our work highlights that the presence of NKG2D-expressing cells is not always a good prognostic marker in advanced tumors, and that more research is needed to fully understand its mechanisms of action and investigate the efficacy and safety of NKG2D-based therapy in colorectal cancer. ABSTRACT: Treating colorectal cancer (CRC) is a major challenge due to the heterogeneous immunological, clinical and pathological landscapes. Immunotherapy has so far only proven effective in a very limited subgroup of CRC patients. To better define the immune landscape, we examined the immune gene expression profile in various subsets of CRC patients and used a mouse model of intestinal tumors to dissect immune functions. We found that the NK cell receptor, natural-killer group 2 member D (NKG2D, encoded by KLRK1) and NKG2D ligand gene expression is elevated in the most immunogenic subset of CRC patients. High level of KLRK1 positively correlated with the mRNA expression of IFNG and associated with a poor survival of CRC patients. We further show that NKG2D deficiency in the Apc(min/+) mouse model of intestinal tumorigenesis led to reduced intratumoral IFNγ production, reduced tumorigenesis and enhanced survival, suggesting that the high levels of IFNγ observed in the tumors of CRC patients may be a consequence of NKG2D engagement. The mechanisms governing the contribution of NKG2D to CRC progression highlighted in this study will fuel discussions about (i) the benefit of targeting NKG2D in CRC patients and (ii) the need to define the predictive value of NKG2D and NKG2D ligand expression across tumor types.