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Recognition of NKG2DLs such as MICA\/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.<\/jats:p>","DOI":"10.3390\/ijms25074126","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T10:11:55Z","timestamp":1712571115000},"page":"4126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0886-2177","authenticated-orcid":false,"given":"Anna","family":"Seller","sequence":"first","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Department of Women\u2019s Health, University Hospital T\u00fcbingen, Calwerstra\u00dfe 7, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-7351","authenticated-orcid":false,"given":"Christian M.","family":"Tegeler","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Health, University Hospital T\u00fcbingen, Calwerstra\u00dfe 7, 72076 T\u00fcbingen, Germany"},{"name":"Department of Peptide-Based Immunotherapy, Institute of Immunology, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Mauermann","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilona","family":"Hagelstein","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Liebel","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3502-382X","authenticated-orcid":false,"given":"Andr\u00e9","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Health, University Hospital T\u00fcbingen, Calwerstra\u00dfe 7, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas S.","family":"Heitmann","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"},{"name":"Department of Peptide-Based Immunotherapy, Institute of Immunology, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Greiner","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Department of Women\u2019s Health, University Hospital T\u00fcbingen, Calwerstra\u00dfe 7, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Hayn","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-8283","authenticated-orcid":false,"given":"Dominik","family":"Dannehl","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Health, University Hospital T\u00fcbingen, Calwerstra\u00dfe 7, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8063-2053","authenticated-orcid":false,"given":"Tobias","family":"Engler","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Health, University Hospital T\u00fcbingen, Calwerstra\u00dfe 7, 72076 T\u00fcbingen, 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Hospital T\u00fcbingen, Otfried-M\u00fcller-Str. 10, 72076 T\u00fcbingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen, R\u00f6ntgenweg 11, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"ref_1","unstructured":"Zentrum f\u00fcr Krebsregisterdaten, R. 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