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.
“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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“With the exception of ovarian cancers (168, 169), in humans, cell surface expression of NKG2DLs has been reported to positively correlates with the outcome in a majority of studied cancers including those of colon/rectum (170, 171), breast (172), pancreas (173), as well as hepatocellular carcinoma (174).”
BackgroundULBP6/RAET1L is an additional human NKG2D ligand
Eagle, R. A., Traherne, J. A., Hair, J. R., Jafferji, I., & Trowsdale, J. (2009) · European Journal of Immunology · doi:10.1002/eji.200939502 · Cited by 120 · see citing works
Self-citationPerturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis
Liu, G., Lu, S., Wang, X., Page, S. T., Higano, C. S., Plymate, S. R., Greenberg, N. M., Sun, S., Li, Z., & Wu, J. D. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69369 · Cited by 119 · see citing works
Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence
Kamimura, H., Yamagiwa, S., Tsuchiya, A., Takamura, M., Matsuda, Y., Ohkoshi, S., Inoue, M., Wakai, T., Shirai, Y., Nomoto, M., et al. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.06.017 · Cited by 118 · see citing works
“In colorectal cancer, a high level of NKG2D expression in tumors is associated with good prognosis, and MICA is a strong independent predictor of long survival [31].”
BackgroundNatural Killer Cells: Tumor Surveillance and Signaling
Guzman, L. G. M., Keating, N., & Nicholson, S. E. (2020) · Cancers · doi:10.3390/cancers12040952 · Cited by 109 · see citing works
Methylation of NKG2D ligands contributes to immune system evasion in acute myeloid leukemia
Raneros, A. B., Martín‐Palanco, V., Fernández, A. F., Rodríguez, R. M. A., Fraga, M. F., López‐Larrea, C., & Suárez-Álvarez, B. (2014) · Genes and Immunity · doi:10.1038/gene.2014.58 · Cited by 101 · see citing works
The immune microenvironment of colorectal cancer
Kennel, K. B., & Greten, F. R. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00872-1 · Cited by 100 · see citing works
NK Cells and Cancer Immunoediting
Guillerey, C., & Smyth, M. J. (2015) · Current topics in microbiology and immunology · doi:10.1007/82_2015_446 · Cited by 97 · see citing works
Human NKG2D-ligands: cell biology strategies to ensure immune recognition
Fernández‐Messina, L., Reyburn, H. T., & Valés‐Gómez, M. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00299 · Cited by 96 · see citing works
“Another level of complexity is that expression of a particular ligand in different types of cancer can be associated with better or worse prognosis (Wu et al., 2004; Li et al., 2009; McGilvray et al., 2009, 2010; Paschen et al., 2009; Nuckel et al., 2010).”
BackgroundTumor-associated autoantibodies as diagnostic and prognostic biomarkers
Heo, C.-K., Bahk, Y. Y., & Cho, E. (2012) · BMB Reports · doi:10.5483/bmbrep.2012.45.12.236 · Cited by 92 · see citing works
“cells expressing NKG2D ligands were decreased with tumor stage progressively (15).”
BackgroundMICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer
Cho, H., Chung, J., Kim, S., Braunschweig, T. A., Kang, T. H., Kim, J., Chung, E. J., Hewitt, S. M., & Kim, J.-H. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-957 · Cited by 89 · see citing works
“Negative controls were processed by omitting the primary antibodies, and TMAs included colorectal cancer positive control tissues [19].”
BackgroundMethodNK Cells: Key to Success of DC-Based Cancer Vaccines?
Lion, E., Smits, E., Berneman, Z. N., & Tendeloo, V. F. V. (2012) · The Oncologist · doi:10.1634/theoncologist.2011-0122 · Cited by 87 · see citing works
“Tumor cell expression of NK cell–related immune evasion or suppression molecules Membrane-bound NKG2DL [158, 169, 176, 177]; soluble NKG2DL [11, 169, 173, 176–181, 185] Predictive parameter for different malignancies”
BackgroundInfluentialMcGilvray, R. W., Eagle, R. A., Rolland, P., Jafferji, I., Trowsdale, J., & Durrant, L. G. (2010) · International Journal of Cancer · doi:10.1002/ijc.25156 · Cited by 88 · see citing works
Self-citationDysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery
Angka, L., Khan, S., Kilgour, M. K., Xu, R. Y., Kennedy, M. A., & Auer, R. C. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081787 · Cited by 81 · see citing works
“Although the ligands for these receptors are poorly defined and a topic of considerable interest, recent work has determined that NKG2D recognizes cell surface glycoproteins (including MHC-class I polypeptide-related sequence A (MICA), MICB, UL16-binding proteins 1–6 (ULPBs)) and NCRs bind heparin sulfate [29,30].”
BackgroundMechanisms of Immunosuppression in Colorectal Cancer
Zhang, Y., Rajput, A., Jin, N. Y., & Wang, J. (2020) · Cancers · doi:10.3390/cancers12123850 · Cited by 81 · see citing works
“Another clinical study has demonstrated that the survival advantage of CRC may differ because of the different expression patterns of two groups of NKG2D ligands (MIC and RAET1G) in the tumor cells, suggesting that some expression signature of NKG2D ligands in tumor cells may inhibit the activation of NK cells and ind…”
BackgroundChrétien, A.-S., Roy, A. L., Vey, N., Prébet, T., Blaise, D., Fauriat, C., & Olive, D. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00122 · Cited by 79 · see citing works
Immunobiology and Conflicting Roles of the Human NKG2D Lymphocyte Receptor and Its Ligands in Cancer
El‐Gazzar, A., Groh, V., & Spies, T. A. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301071 · Cited by 79 · see citing works
“In a colorectal cancer study, MICA was an independent marker of good prognosis for stage I and stage II but not later stage cancers (38).”
BackgroundFang, L., Gong, J., Wang, Y., Liu, R., Li, Z., Wang, Z., Zhang, Y., Zhang, C., Song, C., Yang, A., et al. (2014) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-014-0076-7 · Cited by 76 · see citing works
“In humans, MICA/B is rarely expressed in healthy cells, but a broad expression in carcinoma cells, such as colorectal [17,18], breast [19], pancreatic cancers [20] and hepatocellular carcinoma [21].”
BackgroundDevelopment of NKG2D-based chimeric antigen receptor-T cells for gastric cancer treatment
Tao, K., He, M. Q., Tao, F., Xu, G., Ye, M., Zheng, Y., & Li, Y. (2018) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-018-3670-0 · Cited by 76 · see citing works
Colorectal cancer prevention: Immune modulation taking the stage
Fletcher, R., Wang, Y., Schoen, R. E., Finn, O. J., Yu, J., & Zhang, L. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.12.002 · Cited by 77 · see citing works
Shaler, C. R., Tun‐Abraham, M. E., Skaro, A. I., Khazaie, K., Corbett, A. J., Mele, T. S., Hernandez‐Alejandro, R., & Haeryfar, S. M. M. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-2050-7 · Cited by 73 · see citing works
“NKG2D ligands are highly expressed by CRC tumors, especially in their early stages, but are progressively lost, and their expression levels correlate with patient survival [26].”
BackgroundTriki, H., Charfi, S., Bouzidi, L., Kridis, W. B., Daoud, J., Chaabane, K., Sellami‐Boudawara, T., Rebaï, A., & Cherif, B. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116543 · Cited by 72 · see citing works
Catalán, E., Charni, S., Jaime‐Sánchez, P., Aguiló, J. I., Enrı́quez, J. A., Naval, J., Pardo, J., Villalba, M., & Anel, A. (2015) · OncoImmunology · doi:10.4161/2162402x.2014.985924 · Cited by 67 · see citing works
“This observation suggest that aggressive metastasis could become also resistant to NK cells by losing the expression of ligands for those activating receptors, and this has been reported in some clinical studies.(40) In addition, it has been reported that in vivo, NK cells could lack migration inside the tumor mass, e…”
Cadoux, M., Caruso, S., Pham, S., Gougèlet, A., Pophillat, C., Riou, R., Loesch, R., Colnot, S., Nguyễn, C. T., Caldéraro, J., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.01.017 · Cited by 68 · see citing works
Opposite effects of microchimerism on breast and colon cancer
Kamper‐Jørgensen, M., Biggar, R. J., Tjønneland, A. M., Hjalgrim, H., Kroman, N. T., Rostgaard, K., Stamper, C. L., Olsen, A., Andersen, A. N., & Gadi, V. K. (2012) · European Journal of Cancer · doi:10.1016/j.ejca.2012.02.006 · Cited by 65 · see citing works
“As another example NKG2D-family ligand overexpression represents a tumour immune evasion strategy for most tumours including breast,(39) but is associated with better prognosis in colorectal cancer.(40) If confirmed, our findings may be clinically exploitable as a prescreening test to identify women with a high freque…”
BackgroundMolecular Bases for the Regulation of NKG2D Ligands in Cancer
Huergo-Zapico, L., Acebes‐Huerta, A., López‐Soto, A., Villa-Ãlvarez, M. N., González, A. P., & Gonzalez, S. R. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00106 · Cited by 66 · see citing works
“Moreover, cell-associated NKG2DL expression correlates with the outcome in colorectal (16, 17), breast, (18) and pancreatic cancers (19) and hepatocellular carcinoma (20).”
BackgroundCancer Immunosurveillance and Immunoediting by Natural Killer Cells
Gross, E. T. E., Sunwoo, J. B., & Bui, J. D. (2013) · The Cancer Journal · doi:10.1097/ppo.0000000000000005 · Cited by 65 · see citing works
“In a study of 462 primary colorectal carcinoma tumors, a significant positive correlation between NKG2D ligand expression on the tumor cells and better survival was observed.(91) Importantly, the expression of NKG2D ligands was progressively lower in higher-staged tumors, and this was associated with a decreased immun…”
BackgroundHigh levels of cleaved caspase-3 in colorectal tumour stroma predict good survival
Noble, P. W., Vyas, M., Al‐Attar, A., Durrant, S., Scholefield, J. H., & Durrant, L. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.166 · Cited by 64 · see citing works
“…elective surgical resection of a histologically proven sporadic primary colorectal cancer at the University Hospital, Nottingham, UK (Table 1; Durrant et al, 2003; Watson et al, 2005; Watson et al, 2006a; Duncan et al, 2007; Ullenhag et al, 2007; McGilvray et al, 2009; Simpson et al, 2010).”
BackgroundSelf-citationBalanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion
Myers, J. A., Schirm, D. K., Bendzick, L. E., Hopps, R., Selleck, C., Hinderlie, P., Felices, M., & Miller, J. S. (2022) · JCI Insight · doi:10.1172/jci.insight.150079 · Cited by 63 · see citing works
The Paradoxical Role of NKG2D in Cancer Immunity
Sheppard, S., Ferry, A., Guedes, J., & Guerra, N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01808 · Cited by 61 · see citing works
“One common feature is the heterogeneity in ligand expression between cancer types and individuals (42, 45, 47, 51), which hinders the prognostic value of NKG2D ligands in clinical assessment.”
BackgroundRegulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression
Jones, A. B., Rocco, A., Lamb, L. S., Friedman, G. K., & Hjelmeland, A. B. (2022) · Cancers · doi:10.3390/cancers14092339 · Cited by 62 · see citing works
Loss of natural killer T cells promotes pancreatic cancer in LSL ‐KrasG12D/+ mice
Janakiram, N. B., Mohammed, A., Bryant, T., Ritchie, R. L., Stratton, N. C., Jackson, L. A., Lightfoot, S. A., Benbrook, D. M., Asch, A. S., Lang, M. L., et al. (2017) · Immunology · doi:10.1111/imm.12746 · Cited by 61 · see citing works
Yun, C., Hong, J., & Yoon, A. R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.953410 · Cited by 59 · see citing works
Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXRγ activation
Leung, W., Vong, Q. P., Lin, W., Janke, L. J., Chen, T., & Leung, W. H. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20122292 · Cited by 59 · see citing works
“The ligand expression, however, progressively decreases in later stages of the disease, and the level of expression correlates with patient survival (McGilvray et al., 2009).”
BackgroundExploiting natural killer group 2D receptors for CAR T-cell therapy
Demoulin, B., Cook, W. J., Murad, J., Graber, D. J., Sentman, M.-L., Lonez, C., Gilham, D. E., Sentman, C. L., & Agaugué, S. (2017) · Future Oncology · doi:10.2217/fon-2017-0102 · Cited by 58 · see citing works
Mucosa-associated invariant T cells in malignancies: a faithful friend or formidable foe?
Haeryfar, S. M. M., Shaler, C. R., & Rudak, P. T. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2132-1 · Cited by 58 · see citing works
“It binds to proteins encoded by the MHC class I polypeptide-related sequence (MIC) A and B loci and members of the UL16-binding protein/ retinoic acid early transcript 1 (ULBP/RAET1) family [66, 67].”
Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer
Mimura, K., Kamiya, T., Shiraishi, K., Kua, L., Shabbir, A., So, J. B. Y., Yong, W. P., Suzuki, Y., Yoshimoto, Y., Nakano, T., et al. (2014) · International Journal of Cancer · doi:10.1002/ijc.28780 · Cited by 56 · see citing works
Gowen, B. G., Chim, B., Marceau, C. D., Greene, T. T., Burr, P., Gonzalez, J. R., Hesser, C. R., Dietzen, P. A., Russell, T. A., Iannello, A., et al. (2015) · eLife · doi:10.7554/elife.08474 · Cited by 52 · see citing works
“In the case of NKG2Dmediated tumor recognition, published results suggest that one mechanism of tumor immune evasion is the loss or decreased expression of NKG2D ligands (Guerra et al., 2008; McGilvray et al., 2009).”
BackgroundT-Cell-Based Immunotherapy for Osteosarcoma: Challenges and Opportunities
Wang, Z., Li, B., Ren, Y., & Ye, Z. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00353 · Cited by 73 · see citing works
“A positive correlation between NKG2D-L expression and improved clinical outcomes has been documented in various solid tumors (138).”
BackgroundZaghi, E., Calvi, M., Marcenaro, E., Mavilio, D., & Vito, C. D. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0718-300r · Cited by 53 · see citing works
Assessment of the humoral immune response to cancer
Murphy, M., O’Leary, J. J., & Cahill, D. J. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.01.021 · Cited by 51 · see citing works
“[11] McGilvray RW, Eagle RA,Watson NF, Al-Attar A, Ball G, Jafferji I, et al.”
BackgroundExploiting NK Cell Surveillance Pathways for Cancer Therapy
Barrow, A. D., & Colonna, M. (2019) · Cancers · doi:10.3390/cancers11010055 · Cited by 49 · see citing works
Guma, S. R., Lee, D. A., Yu, L., Gordon, N. B., Hughes, D. P. M., Stewart, J., Wang, W., & Kleinerman, E. S. (2013) · Pediatric Blood & Cancer · doi:10.1002/pbc.24801 · Cited by 49 · see citing works
“Usually decreased NKG2DL expression correlates with disease progression [33].”
BackgroundNieto-Velázquez, N. G., Torres-Ramos, Y. D., Muñoz-Sánchez, J. L., Espinosa-Godoy, L., Gómez-Cortés, S., Moreno, J. G., & Moreno‐Eutímio, M. A. (2016) · Translational Oncology · doi:10.1016/j.tranon.2016.07.003 · Cited by 49 · see citing works
“There were no significant differences in the absolute numbers or percentages of white blood cells, CD4+T cells, CD8+T cells, B cells, NK cells,monocytes, eosinophils, neutrophils, and basophils (Tables 3 and 4).”
BackgroundThe Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer
Tan, G., Spillane, K. M., & Maher, J. F. (2023) · Biology · doi:10.3390/biology12081079 · Cited by 47 · see citing works
Vacca, P., Martini, S., Garelli, V., Passalacqua, G., Moretta, L., & Mingari, M. C. (2012) · European Journal of Immunology · doi:10.1002/eji.201242783 · Cited by 45 · see citing works
Vyas, M., Reinartz, S., Hoffmann, N., Reiners, K. S., Lieber, S., Jansen, J. M., Wagner, U. A. G., Müller, R., & von Strandmann, E. P. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1339854 · Cited by 44 · see citing works
NK Cell-Based Immunotherapy in Colorectal Cancer
Chiesa, M. D., Setti, C., Giordano, C., Obino, V., Greppi, M., Pesce, S., Marcenaro, E., Rutigliani, M., Provinciali, N., Paleari, L., et al. (2022) · Vaccines · doi:10.3390/vaccines10071033 · Cited by 43 · see citing works
Huyan, T., Gao, L., Gao, N., Wang, C., Guo, W., Zhou, X., & Li, Q. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315177 · Cited by 43 · see citing works
“Exhausted anti-tumor immune function has been reported in numerous tumors, including breast cancer, lung cancer, colon cancer [8], kidney cancer, pancreatic cancer, ovarian cancer [9], glioma, and melanoma [10].”
BackgroundShiraishi, K., Mimura, K., Kua, L., Koh, V., Siang, L. K., Nakajima, S., Fujii, H., Shabbir, A., Yong, W. P., So, J. B. Y., et al. (2016) · Journal of Gastroenterology · doi:10.1007/s00535-016-1197-x · Cited by 43 · see citing works
Astragaloside III Enhances Anti-Tumor Response of NK Cells by Elevating NKG2D and IFN-γ
Chen, X., Chen, X., Gao, J., Yang, H. N., Duan, Y., Feng, Y., He, X., Gong, X., Wang, H., Wu, X., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00898 · Cited by 43 · see citing works
“Clinical investigations have shown that high levels of NKG2D ligands on tumor cells predict favorable prognosis (Lanier, 2015), whereas reduced expression of NKG2D usually correlates with strong prognostic relevance in patients (McGilvray et al., 2009).”
Siew, Y.-Y., Neo, S.-Y., Yew, H.-C., Lim, S.-W., Ng, Y.-C., Lew, S.-M., Seetoh, W.-G., Seow, S.-V., & Koh, H. (2015) · International Immunology · doi:10.1093/intimm/dxv041 · Cited by 41 · see citing works
Tsukagoshi, M., Wada, S., Yokobori, T., Altan, B., Ishii, N., Watanabe, A., Kubo, N., Saito, F., Araki, K., Suzuki, H., et al. (2015) · Cancer Science · doi:10.1111/cas.12853 · Cited by 41 · see citing works
Zhang, Z., Su, T., He, L., Wang, H., Ji, G., Liu, X., Zhang, Y., & Dong, G. (2011) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.226.59 · Cited by 38 · see citing works
Fernández‐Messina, L., Ashiru, O., Agüera‐González, S., Reyburn, H. T., & Valés‐Gómez, M. (2011) · Journal of Cell Science · doi:10.1242/jcs.076042 · Cited by 35 · see citing works
The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy
Wei, L., Xiang, Z., & Zou, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417545 · Cited by 34 · see citing works
“Furthermore, high expression of NKG2D-L was associated with a good prognosis and improved tumor invasion in cancer patients [36,37].”
BackgroundLoss of CD 155 expression predicts poor prognosis in hepatocellular carcinoma
Qü, P., Huang, X., Zhou, X., Lu, Z.-M., Liu, F., Shi, Z., Lü, L., Wu, Y., & Chen, Y. (2014) · Histopathology · doi:10.1111/his.12584 · Cited by 33 · see citing works
“It has been demonstrated that the low expression levels of NK cell activation ligands such as major histocompatibilty complex (MHC) class I polypeptiderelated sequence A (MICA), MHC class I polypeptiderelated sequence B (MICB) and UL16 binding protein 1 (ULBP1) on tumour cells are associated with the progression of ca…”
BackgroundPurine nucleotide metabolism regulates expression of the human immune ligand MICA
McCarthy, M. T., Moncayo, G., Hiron, T. K., Jakobsen, N. A., Valli, A., Soga, T., Adam, J., & O’Callaghan, C. A. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.809459 · Cited by 33 · see citing works
“These results are consistent with observational studies of NKG2D ligand expression in disparate settings from malignancy (5) to viral infection (6, 7) and physiological cell proliferation (8, 9).”
BackgroundResultImmunotherapeutic targeting of activating natural killer cell receptors and their ligands in cancer
Peipp, M., Klausz, K., Boje, A. S., Zeller, T., Zielonka, S., & Kellner, C. (2022) · Clinical & Experimental Immunology · doi:10.1093/cei/uxac028 · Cited by 32 · see citing works
Ribeiro, C. H., Kramm, K., Gálvez‐Jirón, F., Pola-Véliz, V., BUSTAMANTE, M., Contreras, H. R., Sabag, A., Garrido‐Tapia, M., Hernández, C., ZÚÑIGA, R., et al. (2015) · Oncology Reports · doi:10.3892/or.2015.4510 · Cited by 32 · see citing works
“In colorectal and pancreatic cancers, MICA was detected as an independent marker of favorable prognosis for stages I and II, but not later stages of the disease (15,45).”
BackgroundCrystal Structure of the Cowpox Virus-Encoded NKG2D Ligand OMCP
Lazear, E., Peterson, L. W., Nelson, C. A., & Fremont, D. H. (2012) · Journal of Virology · doi:10.1128/jvi.01948-12 · Cited by 31 · see citing works
“Tumor cells expressing high levels of NKG2DLs are more susceptible to immune clearance, and NKG2DLs have been implicated in immunoediting of tumor cells (14, 15).”
BackgroundZitvogel, L., Kepp, O., Aymeric, L., Ma, Y., Locher, C., Delahaye, N. F., André, F., & Kroemer, G. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1003 · Cited by 30 · see citing works
Krijgsman, D., Roelands, J. P., Andersen, M. N., Wieringa, C. H. L. A., Tollenaar, R. A. �. �., Hendrickx, W., Bedognetti, D., Hokland, M., & Kuppen, P. J. K. (2020) · Molecular Immunology · doi:10.1016/j.molimm.2020.10.012 · Cited by 30 · see citing works
Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis
Ruan, G., Xie, H., Zhu, L., Ge, Y., Lin, Y., Liao, C., Gong, Y., & Shi, H. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.762514 · Cited by 29 · see citing works
“In humans, primary tumors and tumor cell lines express NKG2D ligands at a high frequency (McGilvray et al., 2009).”
BackgroundResultInfluentialMolecular Mechanisms of Tumor Immunomodulation in the Microenvironment of Colorectal Cancer
Plundrich, D., Chikhladze, S., Fichtner‐Feigl, S., Feuerstein, R., & Briquez, P. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052782 · Cited by 31 · see citing works
“ligands are not generally expressed in healthy cells but are upregulated during carcinogenesis [40,41].”
BackgroundZhang, Y., Liang, K., Zhou, X., Zhang, X., Xu, H. J., Dai, H., Song, X., Yang, X., Liu, B., Shi, T., et al. (2023) · Cancer Science · doi:10.1111/cas.15828 · Cited by 27 · see citing works
Targeting p53 for immune modulation: Exploring its functions in tumor immunity and inflammation
Wu, H. H., Leng, S., Eisenstat, D. D., Sergi, C. M., & Leng, R. P. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217614 · Cited by 26 · see citing works
Sanchez, C. E., Dowlati, E. P., Geiger, A. E., Chaudhry, K., Tovar, M. A., Bollard, C. M., & Cruz, C. C. (2020) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2020.09.030 · Cited by 26 · see citing works
“Bottom, in blue: NK cell activating receptor ligands are expressed by numerous malignancies [45-60,62,242-247], and these tumors engage NK-activating receptors, some of which associate with ITAM-containing DAP10 and DAP12 to mediate NK cell activation via proteins such as Vav1 and PLCγ2.”
BackgroundOliviero, B., Varchetta, S., Mele, D., Pessino, G., Maiello, R., Falleni, M., Tosi, D., Donadon, M., Soldani, C., Franceschini, B., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2035919 · Cited by 26 · see citing works
“Furthermore, soluble MICA and MICB that might block NKG2D receptor interaction with its cellular ligands are found in the sera of cancer patients, which frequently correlate with poor prognosis and impaired T and NK cell function.(19,28) Recently, Ferrari de Andrade et al.”
BackgroundCancer Immunoediting: Elimination, Equilibrium, and Immune Escape in Solid Tumors
Wilczyński, J. R., & Nowak, M. (2022) · Experientia supplementum · doi:10.1007/978-3-030-91311-3_1 · Cited by 26 · see citing works
Li, B., Zhu, X., Ge, J., Zhang, H., Gao, Y., Bao, X., Dai, X., Du, Z., Tu, X., Zhou, T., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.05.026 · Cited by 26 · see citing works
Insights Into Cetacean Immunology: Do Ecological and Biological Factors Make the Difference?
Marsili, L., Guardo, G. D., Mazzariol, S., & Casini, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01219 · Cited by 25 · see citing works
“(37) reported that NKG2D ligands were highly expressed in lymph node metastasis of stage I colorectal cancer samples, but they were expressed in lower amounts in Stage II, III, or IV tumors.”
BackgroundKIM, G. R., Ha, G., BAE, J.-H., Oh, S., Kim, S., & Kang, C. (2015) · Oncology Letters · doi:10.3892/ol.2015.2918 · Cited by 25 · see citing works
“High expression of MIC or RAET1G has been shown to be associated with prolonged survival of patients with colorectal tumors (38).”
Singh, S., & Banerjee, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-62081-0 · Cited by 25 · see citing works
PRL-3 Mediates the Protein Maturation of ULBP2 by Regulating the Tyrosine Phosphorylation of HSP60
Leung, W., Vong, Q. P., Lin, W., Bouck, D. C., Wendt, S., Sullivan, E., Li, Y., Bari, R., Chen, T., & Leung, W. H. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1400817 · Cited by 24 · see citing works
“Many reports have suggested that the expression level of NKG2DLs on tumor cells directly correlates with tumor susceptibility to NK cytolysis (2) and with cancer patient survival rate (3).”
BackgroundLebrec, H. N., Brennan, F. R., Haggerty, H. G., Herzyk, D., Kamperschroer, C., Maier, C. C., Ponce, R. A., Preston, B. D., Weinstock, D., & Mellon, R. D. (2015) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2015.12.018 · Cited by 24 · see citing works
Hu, J., Bernatchez, C., Zhang, L., Xia, X., Kleinerman, E. S., Hung, M., Hwu, P., & Li, S. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0234 · Cited by 24 · see citing works
“In colorectal cancer patients, large amounts of the NKG2D ligands MICA and ULBP2, in particular, were shown to correlate with a longer survival time (10).”
Harnessing Natural Killer Cells in Cancer Immunotherapy: A Review of Mechanisms and Novel Therapies
St‐Pierre, F., Bhatia, S., & Chandra, S. (2021) · Cancers · doi:10.3390/cancers13081988 · Cited by 23 · see citing works
“Nonetheless, tumor cells have developed mechanisms to evade destruction by NK cells; namely, certain tumor cells shed “decoy” NKG2D soluble ligands to saturate the NKG2D receptor on the NK cells to prevent the destruction of the tumor cells [16].”
Background
- 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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