NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting.
OBJECTIVE
NKG2D (natural killer group 2, member D) binds to cellular ligands of the MIC and ULBP/RAET family. These ligands have restricted expression in normal tissue, but are frequently expressed on primary tumors. The role of NKG2D ligands is thought to be important in carcinogenesis but its prognostic effect has not been investigated in such a large cohort.


METHODS
In our study, 462 primary colorectal tumors were screened for the expression of all MIC/ULBP/RAET proteins and NK cell infiltration. Tumor microarray technology was used for the purpose of this investigation.


RESULTS
NKG2D ligands were expressed by the majority of colorectal tumors; however, the level of expression varied considerably. High expression of MIC (68 versus 56 months) or RAET1G (74 versus 62 months) showed improved patient survival. Tumors expressing high levels of MIC and RAET1G showed improved survival of 77 months over tumors that expressed high levels of one ligand or low levels of both. High-level expression of all ligands was frequent in tumor-node-metastasis stage I tumors, but became progressively less frequent in stages II, III, and IV tumors. Expression of MIC was correlated with NK cellular infiltration.


CONCLUSIONS
The observations presented are consistent with an immunoediting mechanism that selects tumor cells that have lost or reduced their expression of NKG2D ligands. The combination of MIC and tumor-node-metastasis stage was found to be the strongest predictor of survival, splitting patients into eight groups and suggesting prognostic value in clinical assessment. Of particular interest were stage I patients with low expression of MIC who had a similar survival to stage III patients, and may be candidates for adjuvant therapy.
Academic Division of Clinical Oncology, University of Nottingham, City Hospital Campus, Section of Gastrointestinal Surgery, Queen's Medical Centre, John Van Geest Research Centre, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom.
Roger W
RW
McGilvray
Robert A
RA
Eagle
Nicholas F S
NF
Watson
Ahmad
A
Al-Attar
Graham
G
Ball
Insiya
I
Jafferji
John
J
Trowsdale
Lindy G
LG
Durrant
D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis* / Q000235:genetics*; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D013997:Time Factors; D016896:Treatment Outcome
C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K