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NKG2D Ligand Expression in Human Colorectal Cancer Reveals Associations with Prognosis and Evidence for Immunoediting
Open accessAbstract
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. (Clin Cancer Res 2009;15(22):69937002)
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“These findings may be one explanation for why expression of NKG2D ligands in some cancers is insufficient to trigger NKG2D-dependent elimination of tumors (Jinushi et al., 2003; Guerra et al., 2008; McGilvray et al., 2009; Hilpert et al., 2012).”
From p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells (2013) · cites this paper as McGilvray et al., 2009
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“In both solid tumours and haematological malignancies, higher levels of MICA/MICB expression were associated with increased cytotoxic activity and more favourable outcome (Chen et al., 2013; Lu et al., 2010; McGilvray et al., 2009).”
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“Tumor cells also have the capacity to impair cytotoxicity of peripheral NK cells through modulating the expression of activating and/or inhibitory receptors.(8-10) Despite the fact that NK cells are dramatically enriched in liver and the significance of NK cells-mediated cytotoxic and immunoregulatory role in antitumo…”
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Targeting NKG2D/NKG2DL axis in multiple myeloma therapy
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“Upregulation of NKG2DLs on cancer cells enhance NK cell infiltration and promote cancer cytotoxicity (2, 3).”
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The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology
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“Paradoxically, we also observed that higher expression of klrk1 (NKG2D) was associated with impaired overall survival in ccRCC, in spite of previous reports that indicate that NKG2DLs shed by tumors promote either downregulation or blockade of NKG2D.(32,37,50,69) We observed that indeed, PBNK from ccRCC patients expre…”
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“Colorectal tumors express several NKG2D ligands; however, their level varies considerably and there is no consistent evidence of their prognostic value [34, 35].”
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Talaat, I. M., Elemam, N. M., Zaher, S., & Saber-Ayad, M. M. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.955599 · Cited by 15
“Hence, ligands of the activating receptor NKG2D were detected in the early stages of CRC, but as an immune evasion strategy, their expression decreased upon disease progression (146).”
BackgroundExpression of MHC class I polypeptide-related sequence A (MICA) in colorectal cancer
Espinoza, I., Agarwal, S., Sakiyama, M., Shenoy, V., Orr, W. S., Diffalha, S. A., Prizment, A. E., Varambally, S., Manne, U., & Gomez, C. R. (2021) · Frontiers in Bioscience-Landmark · doi:10.52586/4986 · Cited by 14
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“The expression of NKG2D ligands has been associated with a good prognosis in patients with colon cancer.(20) Thus, these results suggest that the upregulation of NKG2D ligand expression might improve the prognosis of patients with colon cancer.”
BackgroundMICA-specific nanobodies for diagnosis and immunotherapy of MICA+ tumors
Verhaar, E. R., Knoflook, A., Pishesha, N., Liu, X., van Keizerswaard, W. J. C., Wucherpfennig, K. W., & Ploegh, H. L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1368586 · Cited by 12
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“These studies have also recommended the use of this biomarker as a diagnostic tumor marker for these types of cancers [21, 35, 36].”
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“Immunohistochemistry for NKG2D ligands consistently demonstrated a predominantly diffuse cytoplasmic and partial membranous staining pattern, as reported previously (Groh et al. 1999; McGilvray et al. 2010; McGilvray et al. 2009; Eagle et al. 2009a; Eagle et al. 2009b).”
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“Besides, NKG2D ligands were highly enriched on colorectal cancer cells, especially in their early stages, but were progressively lost, and their amount positively correlated with patient survival [111].”
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NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer
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“These observations are in line with recent analyses of ULBP1 mRNA expression in 438 patients with colon adenocarcinoma [33] and of MICA mRNA and protein expression in 96 CRC patients [26], although in contradiction with other MICA-related conclusions [34,35].”
ResultTandem CAR T-cells targeting CD19 and NKG2DL can overcome CD19 antigen escape in B-ALL
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“[5] detected a significant decrease in MICA expression levels with the progression of TNM stages in CRC.”
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“In addition, NKG2D ligand expression is reportedly correlated with better clinical prognosis in CRC.46 In this study, neoadjuvant chemotherapy did not affect the expression of non‐classical MHC class I antigens on CRLM tumor tissues, suggesting that chemotherapeutic agents might not diminish susceptibility to NK cell‐…”
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“NKG2D ligand expression on cancer cells is generally associated with indolent disease progression and prolonged survival in several types of tumour [11], increased ligand shedding may be one mechanism responsible for NKG2D down-regulation, decreased cytotoxic potential and tumour progression, at least when soluble MIC…”
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Espinoza, I. C., Agarwal, S., Sakiyama, M. J., Shenoy, V., Orr, W. S., Diffalha, S. A., Prizment, A. E., Manne, U., & Gómez, C. R. (2021) · Research Square · doi:10.21203/rs.3.rs-311547/v1 · Cited by 8
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Solid tumours: Building bridges to CAR‐T success
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NKG2D Ligands in Cancer Immunotherapy: Target or Not?
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Alloimmune Activation Promotes Anti-Cancer Cytotoxicity after Rat Liver Transplantation
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“This pathway has been previously explored in other oncological settings such as colorectal carcinoma, and the level of tumor NKG2D ligand expression has been associated to HCC response and patient survival [10,35].”
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“Some NKG2D ligands, for example, ULBP/RAET family, were induced by overexpression of three ISGs and correlated with the prognosis of CRC patients [41].”
BackgroundNK Cell-associated Antigen Expression in Retinoblastoma Animal Model
Lee, E. K., Jo, D. H., Kim, J. H., Yu, Y. S., Kim, K., & Kim, J. H. (2012) · Cancer Investigation · doi:10.3109/07357907.2012.743554 · Cited by 4
“MICA expression is reported to be an indicator of good prognosis in colorectal cancer (16, 17), while it was not significantly associated with clinical outcome in breast cancer and ovarian cancer (18, 20).”
BackgroundDiethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis
Dumut, D. C., Hajdúch, M., Zacharias, A. M., Duan, Q., Frydrych, I., Rozankova, Z., Popper, M., Garić, D., Paun, R. A., Centorame, A., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1491450 · Cited by 3
Dormancy in colorectal cancer: The functional core of resistance, metastasis, and relapse
Alvarado-Ortiz, E., Moreno-Londoño, Á. P., & Sarabia-Sánchez, M. Á. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.105081 · Cited by 3
Targeting NKG2D/NKG2DL axis in cancer immunotherapy: mechanisms and therapeutic applications
Wei, H., Xiang, L., Zhou, Y., Huang, Y., Liu, L., & Cao, D. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-025-07650-5 · Cited by 6
“Overall, multi-tumor data indicate that high MICA/B expression correlates with favorable prognosis in patients with cervical cancer, colorectal cancer, and HCC, whereas ULBP1 and ULBP5 are favorably associated with outcomes in cervical and colorectal cancer, respectively [31, 34, 37, 38].”
Soluble forms of immune checkpoints in ovarian cancer
Kovaleva, O. V., Belova, T. P., Kushlinsky, D. N., Korotkova, E. A., Алексеевна, П. П., Gratchev, A. N., Zinoviev, S. V., Терешкина, И. В., Sokolov, N. Y., Kudlay, D. A., et al. (2021) · Russian Clinical Laboratory Diagnostics · doi:10.51620/0869-2084-2021-66-2-80-86 · Cited by 3
Comparative Immunology of Marine Mammals
(2019) · Frontiers research topics · doi:10.3389/978-2-88963-203-9 · Cited by 3
Expression, Prognosis, and Regulation of ULBP1, ULBP2, and ULBP3 in Human Breast CancerPreprint
Zhang, Y., Han, C., Shao, E., Sun, L., & Liu, D. (2021) · Research Square · doi:10.21203/rs.3.rs-574086/v1 · Cited by 3
Anthonydhason, V., Islamagić, E., Leijon, N., Gaarder, J., Martinsson, T., Fransson, S. M., Thorén, F. B., & Umapathy, G. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1739503 · Cited by 2
Yoon, S. E., Park, S., Cho, J., Ryu, K. J., Yandava, B. D., Lee, S., Kim, S. J., & Kim, W. S. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1194315 · Cited by 2
Development in the Study of Natural Killer Cells for Malignant Peritoneal Mesothelioma Treatment
Liu, Y., Wu, H., Su, Y., Wang, Y., & Li, Y. (2024) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2024.0078 · Cited by 2
“67,69,70 Furthermore, gemcitabine treatment can enhance the susceptibility of cells to Fas ligand exposure in vitro through enhanced phosphorylation of c-Jun N-terminal kinase and stress-activated protein kinase pathways.”
Aparicio, C., Queipo, M., Belver, M., Espeso, F., Serna-Pérez, J., Enríquez, L., Acebal, C., Martín‐Muñoz, Á., Valeri, A., Leivas, A., et al. (2025) · Cancers · doi:10.3390/cancers17193186 · Cited by 2
“Regarding the type of tumors used, human cervical and colorectal tumor samples have been previously characterized, revealing that the majority of the NKG2DL were expressed [71,72], and indicating the clinical applicability of our prototype.”
Natural killer cell activity level in colorectal cancer screening in an average risk population
Amankulov, J., Kaidarova, D., Zholdybay, Z., Zagurovskaya, M., Shatkovskaya, O., Ainakulova, A., & Orazgaliyeva, M. (2021) · Archives of Medical Science · doi:10.5114/aoms/142101 · Cited by 2
“In addition, it has been shown that NK cells can be used as a prognostic marker in various carcinomas [10, 11].”
BackgroundLiu, J., Wang, Y., Wei, X., Liu, S., Hu, C., Peng, P., Wu, W., Cai, J., & Sun, H. (2025) · Cellular Oncology · doi:10.1007/s13402-025-01114-0 · Cited by 2
Xiao, J., Wu, J., Deng, F., Liu, C., Chen, Y., Shen, K., Wang, C., Lin, W., Liu, W., Ning, Z., et al. (2026) · Clinical and Translational Medicine · doi:10.1002/ctm2.70657 · Cited by 1
“22 Consequently, we detected the expression levels of MICA and MICB in CRC cells following SLC5A2 silencing or overexpression.”
Soto‐Cruz, I., Zerecero‐Carreón, O., Trejo-Islas, F., Ventura-Gallegos, J. L., Zentella‐Dehesa, A., Weiss‐Steider, B., & Mendoza-Rincón, J. F. (2019) · Journal of Carcinogenesis & Mutagenesis · doi:10.4172/2157-2518.1000329 · Cited by 1
Kim, M.-S., Jeon, S., Lee, H. J., Ri, H.-S., Cho, A.-R., Park, E. J., Yeo, J., Kim, J.-H., & Lee, J. (2024) · BMC Oral Health · doi:10.1186/s12903-024-04873-8 · Cited by 1
“Numerous recent investigations imply that the degree of NKG2D ligand expression in tumors could function as an indicator for forecasting patient prognosis [10–12].”
BackgroundResultInfluentialCharacterisation of anti-glycan monoclonal antibodies
Noble, P. W. (2011) · Nottingham ePrints (University of Nottingham)
Hu, J. (2012) · Digital Commons-TMC (Texas Medical Center)
Mechanisms of p53-mediated intrinsic and extrinsic tumor suppression
Li, H. (2014) · Figshare
Mechanisms of p53-mediated Intrinsic and Extrinsic Tumor Suppression
Selivanova, G., Höglund, P., Piaggio, G., Elena, R., Pereira, T., Wright, A. R., Wadelius, C., & Universitit, U. (2014)
The Effects of Folic Acid Supplementation on Natural Killer Cell Activity in an Animal Model
Warzyszynska, J. (2015) · TSpace (University of Toronto)
Development of a model system to study nk cell hyporesponsiveness
Romera‐Cárdenas, G. (2014) · Dialnet (Universidad de la Rioja)
ULBP5 is a Susceptibility Gene for Henoch-Schönlein Purpura in Chinese PopulationPreprint
Liu, Y., Yan, H., Tao, Y., Chen, W., Liang, J., Huang, H., Xu, X., Ding, F., Jin, Y., Jian, W., et al. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3963794
Khamarudin, F., Muhamad, M., Ibahim, M. J., Zain, W. N. I. W. M., Ridzuan, N. R. A., Aziz, M. A., & Rahim, S. A. (2022) · Research Square · doi:10.21203/rs.3.rs-1787033/v1
Zitvogel, L., Kepp, O., Aymeric, L., Ma, Y., Locher, C., Delahaye, N. F., André, F., & Kroemer, G. (2023) · doi:10.1158/0008-5472.22385201
Zitvogel, L., Kepp, O., Aymeric, L., Ma, Y., Locher, C., Delahaye, N. F., André, F., & Kroemer, G. (2023) · doi:10.1158/0008-5472.22385201.v1
Xiao, C., Wang, W., Zhang, Y., Huang, T., Chen, C., Liu, B., Liu, C., Yang, Y., Lu, F., & Zhu, Q. K. (2025) · Biomolecules · doi:10.3390/biom16010047
A novel antibody targeting the human MICA α3 domain enhances NK cell activity in vitro
Lv, Y., Jin, Z., & Lou, J. (2025) · Letters in Drug Design & Discovery · doi:10.1016/j.lddd.2026.100330
Elaboration de nouvelles stratégies d'immunothérapie dans les leucémies aigües
Roy, A. L. (2015) · theses.fr (ABES) · doi:10.70675/fda42f6dz8d29z4ca9za484zccec301cfb1d
Mécanismes d'immunosurveillance NKG2D et DNAM-1 dans le carcinome hépatocellulaire
Cadoux, M. (2019) · theses.fr (ABES) · doi:10.70675/a6660468zb747z4a0czb963z900d06687ec7
Rôle de LECT2 dans les maladies stéatosiques non alcooliques du foie
Pham, S. (2020) · theses.fr (ABES) · doi:10.70675/3693bfe6z9d91z4045za9a9zc37497dc9c1b
Introduction to immunity in cancer
Vishwakarma, A., Sah, R., Kumar, P., Hasan, F., Mandlik, D., & Ansari, M. D. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-41551-7.00001-1
Epigenetic modulation of NKG2D ligands enhances NKG2D-CAR T cell efficacy in neuroblastoma
Navarro‐Zapata, A., Santisteban, M. O. D., Zapata, R. M. R., Ibáñez-Navarro, M., Villa, L. C., de la Hoz, M., Romero, A., Mestre‐Durán, C., Al‐Akioui‐Sanz, K., Bareke, H., et al. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08685-y
“Besides heterogeneity, low or null expression of NKG2DLs correlates with decreased OS, MYCN amplification [44] and reduced NK infiltration [36, 45–47].”
Kuramitsu, S., Ohno, M., & Fujita, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1877232
Selective estrogen receptor degraders and their effect on the breast cancer immune microenvironment
Young, K. S., & Fanning, S. W. (2026) · Journal of Clinical Investigation · doi:10.1172/jci207633
“Engagement of NK cell receptors, including NKG2D, NKp46, and CD16, can trigger direct cell killing (131, 132).”
Metadata
- Authors
- McGilvray, R. W., Eagle, R. A., Watson, N. F. S., Al-Attar, A., Ball, G., Jafferji, I., Trowsdale, J., & Durrant, L. G.
- Affiliations
- University of Nottingham (GB)
- Authors' Affiliations: 1Academic Division of Clinical Oncology, University of Nottingham, City Hospital Campus, 2Section of Gastrointestinal Surgery, Queen's Medical Centre, 3John Van Geest Research Centre, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom, and 4Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrookes Hospital, Cambridge, United Kingdom
- Venue
- Clinical Cancer Research
- Published
- 2009-11-11
- Volume
- 15
- Issue
- 22
- Pages
- 6993-7002
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2778653
- OpenAlex
- W2101699880
- Cited by
- 196
- References
- 46
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 8 · 2023: 13 · 2022: 18 · 2021: 13 · 2020: 13 · 2019: 13 · 2018: 8 · 2017: 10 · 2016: 6 · 2015: 17 · 2014: 18 · 2013: 14 · 2012: 10
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Nottingham Trent University's Institutional Repository (Nottingham Trent Repository) (submittedVersion)
- Funders
- Cancer Research UK (A7607)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- NKG2D ligands, colorectal cancer, NK cell infiltration, immunoediting, prognostic factors, patient survival, tumor stage, adjuvant therapy
- MeSH terms
- Aged, Female, Humans, Immunohistochemistry, Ligands, Male, Middle Aged, Models, Theoretical, Neoplasm Metastasis, Prognosis, Time Factors, Colorectal Neoplasms, Cohort Studies, Proportional Hazards Models, Treatment Outcome, Disease-Free Survival, Oligonucleotide Array Sequence Analysis, NK Cell Lectin-Like Receptor Subfamily K
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