NKG2D Ligand Expression in Human Colorectal Cancer Reveals Associations with Prognosis and Evidence for Immunoediting

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2009 Oct 29

PMID 19861434

Citations 103

Authors

Roger W McGilvray

Robert A Eagle

Nicholas F S Watson

Ahmad Al-Attar

Graham Ball

Insiya Jafferji

John Trowsdale

Lindy G Durrant

Affiliations

Soon will be listed here.

Abstract

Purpose: 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.

Experimental Design: 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.

Conclusion: 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.

Citing Articles

Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis.

Dumut D, Hajduch M, Zacharias A, Duan Q, Frydrych I, Rozankova Z Front Immunol. 2025; 16:1491450.

PMID: 40013140 PMC: 11860975. DOI: 10.3389/fimmu.2025.1491450.

Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization.

Chen S, Zhu H, Jounaidi Y Signal Transduct Target Ther. 2024; 9(1):302.

PMID: 39511139 PMC: 11544004. DOI: 10.1038/s41392-024-02005-w.

NKG2D (Natural Killer Group 2, Member D) ligand expression and ameloblastoma recurrence: a retrospective immunohistological pilot study.

Kim M, Jeon S, Lee H, Ri H, Cho A, Park E BMC Oral Health. 2024; 24(1):1102.

PMID: 39289711 PMC: 11409757. DOI: 10.1186/s12903-024-04873-8.

Natural Killer cells at the frontline in the fight against cancer.

Coenon L, Geindreau M, Ghiringhelli F, Villalba M, Bruchard M Cell Death Dis. 2024; 15(8):614.

PMID: 39179536 PMC: 11343846. DOI: 10.1038/s41419-024-06976-0.

Nanobody-based CAR NK cells for possible immunotherapy of MICA tumors.

Verhaar E, van Keizerswaard W, Knoflook A, Balligand T, Ploegh H PNAS Nexus. 2024; 3(5):pgae184.

PMID: 38756234 PMC: 11096969. DOI: 10.1093/pnasnexus/pgae184.

References

Coudert J, Zimmer J, Tomasello E, Cebecauer M, Colonna M, Vivier E . Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood. 2005; 106(5):1711-7. DOI: 10.1182/blood-2005-03-0918. View

Guerra N, Tan Y, Joncker N, Choy A, Gallardo F, Xiong N . NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008; 28(4):571-80. PMC: 3528789. DOI: 10.1016/j.immuni.2008.02.016. View

Watson N, Durrant L, Scholefield J, Madjd Z, Scrimgeour D, Spendlove I . Cytoplasmic expression of p27(kip1) is associated with a favourable prognosis in colorectal cancer patients. World J Gastroenterol. 2006; 12(39):6299-304. PMC: 4088137. DOI: 10.3748/wjg.v12.i39.6299. View

Raulet D . Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003; 3(10):781-90. DOI: 10.1038/nri1199. View

Chalupny N, Sutherland C, Lawrence W, Rein-Weston A, Cosman D . ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun. 2003; 305(1):129-35. DOI: 10.1016/s0006-291x(03)00714-9. View

Oppenheim D, Roberts S, Clarke S, Filler R, Lewis J, Tigelaar R . Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat Immunol. 2005; 6(9):928-37. DOI: 10.1038/ni1239. View

Wiemann K, Mittrucker H, Feger U, Welte S, Yokoyama W, Spies T . Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo. J Immunol. 2005; 175(2):720-9. DOI: 10.4049/jimmunol.175.2.720. View

Cerwenka A, Bakker A, McClanahan T, Wagner J, Wu J, Phillips J . Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity. 2000; 12(6):721-7. DOI: 10.1016/s1074-7613(00)80222-8. View

Armeanu S, Bitzer M, Lauer U, Venturelli S, Pathil A, Krusch M . Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 2005; 65(14):6321-9. DOI: 10.1158/0008-5472.CAN-04-4252. View

10.

Smyth M, Swann J, Cretney E, Zerafa N, Yokoyama W, Hayakawa Y . NKG2D function protects the host from tumor initiation. J Exp Med. 2005; 202(5):583-8. PMC: 2212868. DOI: 10.1084/jem.20050994. View

11.

Bacon L, Eagle R, Meyer M, Easom N, Young N, Trowsdale J . Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. J Immunol. 2004; 173(2):1078-84. DOI: 10.4049/jimmunol.173.2.1078. View

12.

Lee J, Lee K, Kim D, Heo D . Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004; 172(12):7335-40. DOI: 10.4049/jimmunol.172.12.7335. View

13.

Eagle R, Traherne J, Ashiru O, Wills M, Trowsdale J . Regulation of NKG2D ligand gene expression. Hum Immunol. 2006; 67(3):159-69. DOI: 10.1016/j.humimm.2006.02.015. View

14.

Stern-Ginossar N, Gur C, Biton M, Horwitz E, Elboim M, Stanietsky N . Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol. 2008; 9(9):1065-73. DOI: 10.1038/ni.1642. View

15.

Hue S, Monteiro R, Berrih-Aknin S, Caillat-Zucman S . Potential role of NKG2D/MHC class I-related chain A interaction in intrathymic maturation of single-positive CD8 T cells. J Immunol. 2003; 171(4):1909-17. DOI: 10.4049/jimmunol.171.4.1909. View

16.

Eagle R, Flack G, Warford A, Martinez-Borra J, Jafferji I, Traherne J . Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G. PLoS One. 2009; 4(2):e4503. PMC: 2637608. DOI: 10.1371/journal.pone.0004503. View

17.

Eagle R, Trowsdale J . Promiscuity and the single receptor: NKG2D. Nat Rev Immunol. 2007; 7(9):737-44. DOI: 10.1038/nri2144. View

18.

McShane L, Altman D, Sauerbrei W, Taube S, Gion M, Clark G . Reporting recommendations for tumor marker prognostic studies (remark). Exp Oncol. 2006; 28(2):99-105. View

19.

Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S . Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998; 4(7):844-7. DOI: 10.1038/nm0798-844. View

20.

Diefenbach A, Jensen E, Jamieson A, Raulet D . Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 2001; 413(6852):165-71. PMC: 3900321. DOI: 10.1038/35093109. View