Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome
Abstract
:1. Introduction
2. Results
2.1. Clinical Characteristics of the Patient Population Studied
2.2. Distribution of sNKG2DL Serum Levels
2.3. sNKG2DL Serum Levels Correlate with TNM Stage
2.4. Range of sNKG2DL Serum Levels According to Tumor Grading and Receptor Status
2.5. Impact of sNKG2DLs on Progression-Free Survival (PFS) and Overall Survival (OS)
2.6. Analysis of NK Cell Function and NKG2D Receptor Expression
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. PBMCs and Cell Lines
4.3. Flow Cytometry Analysis
4.4. Enzyme-Linked Immunosorbent Assay (ELISA)
4.5. Software and Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Zentrum für Krebsregisterdaten, R. Krebsdaten, Brustkrebs. 2023. Available online: https://www.krebsdaten.de/Krebs/DE/Content/Krebsarten/Brustkrebs/brustkrebs_node.html (accessed on 30 July 2023).
- American Cancer Society, Cancer Facts and Figures. 2023. Available online: https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html (accessed on 30 July 2023).
- Dhar, P.; Wu, J.D. NKG2D and its ligands in cancer. Curr. Opin. Immunol. 2018, 51, 55–61. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Han, C.; Shao, E.; Sun, L.; Liu, D. Expression, Prognosis, and Regulation of ULBP1, ULBP2, and ULBP3 in Human Breast Cancer. Preprint 2021. (Version 1). [Google Scholar] [CrossRef]
- Agaugue, S.; Hargreaves, A.; De Sousa, P.; De Waele, P.; Gilham, D. 1179P—The high expression of NKG2D ligands on tumor and the lack of surface expression on healthy tissues provides a strong rationale to support NKG2D-based therapeutic approaches for cancer. Ann. Oncol. 2018, 29, viii420. [Google Scholar] [CrossRef]
- De Kruijf, E.M.; Sajet, A.; van Nes, J.G.; Putter, H.; Smit, V.T.; Eagle, R.A.; Jafferji, I.; Trowsdale, J.; Liefers, G.J.; van de Velde, C.J.; et al. NKG2D ligand tumor expression and association with clinical outcome in early breast cancer patients: An observational study. BMC Cancer 2012, 12, 24. [Google Scholar] [CrossRef] [PubMed]
- Madjd, Z.; Spendlove, I.; Moss, R.; Bevin, S.; Pinder, S.E.; Watson, N.F.S.; Ellis, I.; Durrant, L.G. Upregulation of MICA on high-grade invasive operable breast carcinoma. Cancer Immun. 2007, 7, 17. [Google Scholar] [PubMed]
- Salih, H.R.; Holdenrieder, S.; Steinle, A. Soluble NKG2D ligands: Prevalence, release, and functional impact. Front. Biosci. 2008, 13, 3448–3456. [Google Scholar] [CrossRef]
- Holdenrieder, S.; Stieber, P.; Peterfi, A.; Nagel, D.; Steinle, A.; Salih, H.R. Soluble MICB in malignant diseases: Analysis of diagnostic significance and correlation with soluble MICA. Cancer Immunol. Immunother. 2006, 55, 1584–1589. [Google Scholar] [CrossRef] [PubMed]
- Tamaki, S.; Kawakami, M.; Ishitani, A.; Kawashima, W.; Kasuda, S.; Yamanaka, Y.; Shimomura, H.; Imai, Y.; Nakagawa, Y.; Hatake, K.; et al. Soluble MICB serum levels correlate with disease stage and survival rate in patients with oral squamous cell carcinoma. Anticancer. Res. 2010, 30, 4097–4101. [Google Scholar] [PubMed]
- Wu, J.D.; Higgins, L.M.; Steinle, A.; Cosman, D.; Haugk, K.; Plymate, S.R. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J. Clin. Investig. 2004, 114, 560–568. [Google Scholar] [CrossRef] [PubMed]
- Zhao, Y.K.; Jia, C.M.; Yuan, G.J.; Liu, W.; Qiu, Y.; Zhu, Q.G. Expression and clinical value of the soluble major histocompatibility complex class I-related chain A molecule in the serum of patients with renal tumors. Genet. Mol. Res. 2015, 14, 7233–7240. [Google Scholar] [CrossRef] [PubMed]
- Kshersagar, J.; Damle, M.N.; Bedge, P.; Jagdale, R.; Tardalkar, K.; Jadhav, D.; Jagadale, S.; Toro, Y.; Sharma, R.; Joshi, M.G. Downregulation of MICA/B tumor surface expressions and augmented soluble MICA serum levels correlate with disease stage in breast cancer. Breast Dis. 2022, 41, 471–480. [Google Scholar] [CrossRef] [PubMed]
- Paschen, A.; Sucker, A.; Hill, B.; Moll, I.; Zapatka, M.; Nguyen, X.D.; Sim, G.C.; Gutmann, I.; Hassel, J.; Becker, J.C.; et al. Differential clinical significance of individual NKG2D ligands in melanoma: Soluble ULBP2 as an indicator of poor prognosis superior to S100B. Clin. Cancer Res. 2009, 15, 5208–5215. [Google Scholar] [CrossRef] [PubMed]
- Rebmann, V.; Schütt, P.; Brandhorst, D.; Opalka, B.; Moritz, T.; Nowrousian, M.R.; Grosse-Wilde, H. Soluble MICA as an independent prognostic factor for the overall survival and progression-free survival of multiple myeloma patients. Clin. Immunol. 2007, 123, 114–120. [Google Scholar] [CrossRef] [PubMed]
- Bauer, S.; Groh, V.; Wu, J.; Steinle, A.; Phillips, J.H.; Lanier, L.L.; Spies, T. Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA. Science 1999, 285, 727–729. [Google Scholar] [CrossRef] [PubMed]
- Baragaño Raneros, A.; Suarez-Álvarez, B.; López-Larrea, C. Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention. Oncoimmunology 2014, 3, e28497. [Google Scholar] [CrossRef] [PubMed]
- Schmiedel, D.; Mandelboim, O. NKG2D Ligands-Critical Targets for Cancer Immune Escape and Therapy. Front. Immunol. 2018, 9, 2040. [Google Scholar] [CrossRef]
- Salih, H.R.; Goehlsdorf, D.; Steinle, A. Release of MICB molecules by tumor cells: Mechanism and soluble MICB in sera of cancer patients. Hum. Immunol. 2006, 67, 188–195. [Google Scholar] [CrossRef] [PubMed]
- Mamessier, E.; Sylvain, A.; Bertucci, F.; Castellano, R.; Finetti, P.; Houvenaeghel, G.; Charaffe-Jaufret, E.; Birnbaum, D.; Moretta, A.; Olive, D. Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition. Cancer Res. 2011, 71, 6621–6632. [Google Scholar] [CrossRef] [PubMed]
- Groh, V.; Wu, J.; Yee, C.; Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002, 419, 734–738. [Google Scholar] [CrossRef]
- Salih, H.R.; Rammensee, H.G.; Steinle, A. Cutting edge: Down-regulation of MICA on human tumors by proteolytic shedding. J. Immunol. 2002, 169, 4098–4102. [Google Scholar] [CrossRef]
- Ashiru, O.; Boutet, P.; Fernández-Messina, L.; Agüera-González, S.; Skepper, J.N.; Valés-Gómez, M.; Reyburn, H.T. Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. Cancer Res. 2010, 70, 481–489. [Google Scholar] [CrossRef] [PubMed]
- Raffaghello, L.; Prigione, I.; Airoldi, I.; Camoriano, M.; Levreri, I.; Gambini, C.; Pende, D.; Steinle, A.; Ferrone, S.; Pistoia, V. Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia 2004, 6, 558–568. [Google Scholar] [CrossRef] [PubMed]
- Sheppard, S.; Ferry, A.; Guedes, J.; Guerra, N. The Paradoxical Role of NKG2D in Cancer Immunity. Front. Immunol. 2018, 9, 1808. [Google Scholar] [CrossRef] [PubMed]
- Wiemann, K.; Mittrucker, H.-W.; Feger, U.; Welte, S.A.; Yokoyama, W.M.; Spies, T.; Rammensee, H.-G.; Steinle, A. Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo. J. Immunol. 2005, 175, 720–729. [Google Scholar] [CrossRef] [PubMed]
- Lundholm, M.; Schröder, M.; Nagaeva, O.; Baranov, V.; Widmark, A.; Mincheva-Nilsson, L.; Wikström, P. Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: Mechanism of immune evasion. PLoS ONE 2014, 9, e108925. [Google Scholar] [CrossRef] [PubMed]
- Song, H.; Kim, J.; Cosman, D.; Choi, I. Soluble ULBP suppresses natural killer cell activity via down-regulating NKG2D expression. Cell Immunol. 2006, 239, 22–30. [Google Scholar] [CrossRef] [PubMed]
- Coudert, J.D.; Scarpellino, L.; Gros, F.; Vivier, E.; Held, W. Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 2008, 111, 3571–3578. [Google Scholar] [CrossRef] [PubMed]
- Koch, C.; Kim, Y.; Zöller, T.; Born, C.; Steinle, A. Chronic NKG2D Engagement In Vivo Differentially Impacts NK Cell Responsiveness by Activating NK Receptors. Front. Immunol. 2017, 8, 1466. [Google Scholar] [CrossRef] [PubMed]
- Barrow, A.D.; Cella, M.; Edeling, M.A.; Khan, A.-A.; Cervantes-Barragan, L.; Bugatti, M.; Schmedt, C.; Vermi, W.; Colonna, M. Cutting Edge: PDGF-DD Binding to NKp44 Costimulates TLR9 Signaling and Proinflammatory Cytokine Secretion in Human Plasmacytoid Dendritic Cells. J. Immunol. 2024, 212, 369–374. [Google Scholar] [CrossRef] [PubMed]
- Barrow, A.D.; Edeling, M.A.; Trifonov, V.; Luo, J.; Goyal, P.; Bohl, B.; Bando, J.K.; Kim, A.H.; Walker, J.; Andahazy, M.; et al. Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor. Cell 2018, 172, 534–548.e19. [Google Scholar] [CrossRef] [PubMed]
- Salih, H.R.; Antropius, H.; Gieseke, F.; Lutz, S.Z.; Kanz, L.; Rammensee, H.-G.; Steinle, A. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 2003, 102, 1389–1396. [Google Scholar] [CrossRef] [PubMed]
- Hilpert, J.; Grosse-Hovest, L.; Grünebach, F.; Buechele, C.; Nuebling, T.; Raum, T.; Steinle, A.; Salih, H.R. Comprehensive analysis of NKG2D ligand expression and release in leukemia: Implications for NKG2D-mediated NK cell responses. J. Immunol. 2012, 189, 1360–1371. [Google Scholar] [CrossRef] [PubMed]
- Champsaur, M.; Lanier, L.L. Effect of NKG2D ligand expression on host immune responses. Immunol. Rev. 2010, 235, 267–285. [Google Scholar] [CrossRef] [PubMed]
- Guerra, N.; Tan, Y.X.; Joncker, N.T.; Choy, A.; Gallardo, F.; Xiong, N.; Knoblaugh, S.; Cado, D.; Greenberg, N.R.; Raulet, D.H. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008, 28, 571–580. [Google Scholar] [CrossRef] [PubMed]
- Maccalli, C.; Giannarelli, D.; Chiarucci, C.; Cutaia, O.; Giacobini, G.; Hendrickx, W.; Amato, G.; Annesi, D.; Bedognetti, D.; Altomonte, M.; et al. Soluble NKG2D ligands are biomarkers associated with the clinical outcome to immune checkpoint blockade therapy of metastatic melanoma patients. Oncoimmunology 2017, 6, e1323618. [Google Scholar] [CrossRef] [PubMed]
- Märten, A.; von Lilienfeld-Toal, M.; Büchler, M.W.; Schmidt, J. Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing gammadelta T cell cytotoxicity. Int. J. Cancer 2006, 119, 2359–2365. [Google Scholar] [CrossRef] [PubMed]
- McGilvray, R.W.; Eagle, R.A.; Rolland, P.; Jafferji, I.; Trowsdale, J.; Durrant, L.G. ULBP2 and RAET1E NKG2D ligands are independent predictors of poor prognosis in ovarian cancer patients. Int. J. Cancer 2010, 127, 1412–1420. [Google Scholar] [CrossRef] [PubMed]
- Xu, H.; Wang, G.; Zhu, L.; Liu, H.; Li, B. Eight immune-related genes predict survival outcomes and immune characteristics in breast cancer. Aging 2020, 12, 16491–16513. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Basher, F.; Wu, J.D. NKG2D Ligands in Tumor Immunity: Two Sides of a Coin. Front. Immunol. 2015, 6, 97. [Google Scholar] [CrossRef] [PubMed]
- Waldhauer, I.; Steinle, A. Proteolytic release of soluble UL16-binding protein 2 from tumor cells. Cancer Res. 2006, 66, 2520–2526. [Google Scholar] [CrossRef] [PubMed]
- Roshani, R.; Boroujerdnia, M.G.; Talaiezadeh, A.H.; Khodadadi, A. Assessment of changes in expression and presentation of NKG2D under influence of MICA serum factor in different stages of breast cancer. Tumor Biol. 2016, 37, 6953–6962. [Google Scholar] [CrossRef] [PubMed]
- Zhao, Y.; Chen, N.; Yu, Y.; Zhou, L.; Niu, C.; Liu, Y.; Tian, H.; Lv, Z.; Han, F.; Cui, J. Prognostic value of MICA/B in cancers: A systematic review and meta-analysis. Oncotarget 2017, 8, 96384–96395. [Google Scholar] [CrossRef] [PubMed]
- Shen, J.; Pan, J.; Du, C.; Si, W.; Yao, M.; Xu, L.; Zheng, H.; Xu, M.; Chen, D.; Wang, S.; et al. Silencing NKG2D ligand-targeting miRNAs enhances natural killer cell-mediated cytotoxicity in breast cancer. Cell Death Dis. 2017, 8, e2740. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.; Wang, S.; Xin, J.; Wang, J.; Yao, C.; Zhang, Z. Role of NKG2D and its ligands in cancer immunotherapy. Am. J. Cancer Res. 2019, 9, 2064–2078. [Google Scholar] [PubMed]
- Shiraishi, K.; Mimura, K.; Kua, L.-F.; Koh, V.; Siang, L.K.; Nakajima, S.; Fujii, H.; Shabbir, A.; Yong, W.-P.; So, J.; et al. Inhibition of MMP activity can restore NKG2D ligand expression in gastric cancer, leading to improved NK cell susceptibility. J. Gastroenterol. 2016, 51, 1101–1111. [Google Scholar] [CrossRef] [PubMed]
- Zocchi, M.R.; Camodeca, C.; Nuti, E.; Rossello, A.; Venè, R.; Tosetti, F.; Dapino, I.; Costa, D.; Musso, A.; Poggi, A. ADAM10 new selective inhibitors reduce NKG2D ligand release sensitizing Hodgkin lymphoma cells to NKG2D-mediated killing. Oncoimmunology 2016, 5, e1123367. [Google Scholar] [CrossRef] [PubMed]
- Kaiser, B.K.; Yim, D.; Chow, I.-T.; Gonzalez, S.; Dai, Z.; Mann, H.H.; Strong, R.K.; Groh, V.; Spies, T. Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature 2007, 447, 482–486. [Google Scholar] [CrossRef] [PubMed]
- Ferrari de Andrade, L.; Tay, R.E.; Pan, D.; Luoma, A.M.; Ito, Y.; Badrinath, S.; Tsoucas, D.; Franz, B.; May, K.F., Jr.; Harvey, C.J.; et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 2018, 359, 1537–1542. [Google Scholar] [CrossRef] [PubMed]
- Wu, J. Antibody targeting soluble NKG2D ligand sMIC refuels and invigorates the endogenous immune system to fight cancer. OncoImmunology 2016, 5, e1095434. [Google Scholar] [CrossRef] [PubMed]
- Whalen, K.A.; Rakhra, K.; Mehta, N.K.; Steinle, A.; Michaelson, J.S.; Baeuerle, P.A. Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors. MAbs 2023, 15, 2208697. [Google Scholar] [CrossRef] [PubMed]
- Paczulla, A.M.; Rothfelder, K.; Raffel, S.; Konantz, M.; Steinbacher, J.; Wang, H.; Tandler, C.; Mbarga, M.; Schaefer, T.; Falcone, M.; et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 2019, 572, 254–259. [Google Scholar] [CrossRef] [PubMed]
- Gil Del Alcazar, C.R.; Trinh, A.; Alečković, M.; Jimenez, E.R.; Harper, N.W.; Oliphant, M.U.; Xie, S.; Krop, E.D.; Lulseged, B.; Murphy, K.C.; et al. Insights into Immune Escape during Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer. Cancer Immunol. Res. 2022, 10, 680–697. [Google Scholar] [CrossRef] [PubMed]
- Arjmandi, F.K.; Dogan, B.E. Chapter 13—Neoadjuvant Therapy Response Assessment with Breast MRI, in Advances in Magnetic Resonance Technology and Applications; Pinker, K., Mann, R., Partridge, S., Eds.; Academic Press: Washington, DC, USA, 2022; pp. 229–248. [Google Scholar]
- Dang, X.; Zhang, X.; Gao, Y.; Song, H. Assessment of Neoadjuvant Treatment Response Using Automated Breast Ultrasound in Breast Cancer. J. Breast Cancer 2022, 25, 344–348. [Google Scholar] [CrossRef] [PubMed]
- Janssen, L.M.; Dekker, B.M.D.; Gilhuijs, K.G.A.; van Diest, P.J.; van der Wall, E.; Elias, S.G. MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: A systematic review and meta-analysis. NPJ Breast Cancer 2022, 8, 107. [Google Scholar] [CrossRef]
- Rodenhuis, S.; Mandjes, I.A.M.; Wesseling, J.; van de Vijver, M.J.; Peeters, M.-J.T.D.F.V.; Sonke, G.S.; Linn, S.C. A simple system for grading the response of breast cancer to neoadjuvant chemotherapy. Ann. Oncol. 2010, 21, 481–487. [Google Scholar] [CrossRef] [PubMed]
- Romeo, V.; Accardo, G.; Perillo, T.; Basso, L.; Garbino, N.; Nicolai, E.; Maurea, S.; Salvatore, M. Assessment and Prediction of Response to Neoadjuvant Chemotherapy in Breast Cancer: A Comparison of Imaging Modalities and Future Perspectives. Cancers 2021, 13, 3521. [Google Scholar] [CrossRef] [PubMed]
- Kaidun, P.; Holzmayer, S.J.; Greiner, S.M.; Seller, A.; Tegeler, C.M.; Hagelstein, I.; Mauermann, J.; Engler, T.; Koch, A.; Hartkopf, A.D.; et al. Targeting NKG2DL with Bispecific NKG2D-CD16 and NKG2D-CD3 Fusion Proteins on Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2023, 24, 13156. [Google Scholar] [CrossRef] [PubMed]
- Therneau, T.M.; Lumley, T. Package ‘survival’. R. Top. Doc. 2015, 128, 28–33. Available online: https://repositorium.sdum.uminho.pt/bitstream/1822/84542/1/Emanuel%20Vieira%20Monteiro%20da%20Silva.pdf (accessed on 20 August 2023).
- Kassambara, A.; Kosinski, M.; Biecek, P.; Fabian, S. “Package ‘Survminer’.” Drawing Survival Curves Using ‘ggplot2’ (R Package Version 03 1) 3. 2017. Available online: https://cran.r-project.org/web/packages/survminer/survminer.pdf (accessed on 20 August 2023).
Patient Characteristics (n = 140) | |
---|---|
Age (in years, median [range]) | 56 (26–92) |
Breast cancer subtype (n [%]) | |
NST (no special type) | 137 (98) |
ILC (invasive lobular carcinoma) | 3 (2) |
TNM stage | |
Tumor size (T) (n [%]) | |
T1 | 26 (19) |
T2 | 56 (40) |
T3 | 33 (24) |
T4 | 25 (18) |
Nodal status (N) (n [%]) | |
N0 | 67 (48) |
N+ | 73 (52) |
Distant metastases (M) (n [%]) | |
M0 | 121 (86) |
M1 | 19 (14) |
UICC stages (n [%]) | |
UICC I | 21 (15) |
UICC II | 59 (42) |
UICC III | 41 (29) |
UICC IV | 19 (14) |
Grading (acc. to Elston and Ellis) (n [%]) | |
G1 | 5 (4) |
G2 | 64 (46) |
G3 | 71 (51) |
Receptor status (n [%]) | |
HR+/HER2− | 76 (54) |
HR+/HER2+ | 18 (13) |
HR−/HER2+ | 12 (9) |
TNBC | 34 (24) |
Serum marker levels (mean (±SD)) | |
LDH (U/L, max. 250) | 222.3 (±54) |
CEA (µg/L, max. 5) | 4.3 (±19.4) |
CA 15-3 (kU/L, max. 33) | 22.4 (±28.8) |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Seller, A.; Tegeler, C.M.; Mauermann, J.; Schreiber, T.; Hagelstein, I.; Liebel, K.; Koch, A.; Heitmann, J.S.; Greiner, S.M.; Hayn, C.; et al. Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome. Int. J. Mol. Sci. 2024, 25, 4126. https://doi.org/10.3390/ijms25074126
Seller A, Tegeler CM, Mauermann J, Schreiber T, Hagelstein I, Liebel K, Koch A, Heitmann JS, Greiner SM, Hayn C, et al. Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome. International Journal of Molecular Sciences. 2024; 25(7):4126. https://doi.org/10.3390/ijms25074126
Chicago/Turabian StyleSeller, Anna, Christian M. Tegeler, Jonas Mauermann, Tatjana Schreiber, Ilona Hagelstein, Kai Liebel, André Koch, Jonas S. Heitmann, Sarah M. Greiner, Clara Hayn, and et al. 2024. "Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome" International Journal of Molecular Sciences 25, no. 7: 4126. https://doi.org/10.3390/ijms25074126