{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:17:29Z","timestamp":1790900249700,"version":"4.1.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Br J Cancer"],"published-print":{"date-parts":[[2020,5,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The role of different subtypes of tumour infiltrating lymphocytes (TILs) in breast ductal carcinoma in situ (DCIS) is still poorly defined. This study aimed to assess the prognostic significance of B and T lymphocytes and immune checkpoint proteins expression in DCIS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A well characterised DCIS cohort (<jats:italic>n<\/jats:italic>\u2009=\u2009700) with long-term follow-up comprising pure DCIS (<jats:italic>n<\/jats:italic>\u2009=\u2009508) and DCIS mixed with invasive carcinoma (IBC;<jats:italic>n<\/jats:italic>\u2009=\u2009192) were stained immunohistochemically for CD20, CD3, CD4, CD8, FOXP3, PD1 and PDL1. Copy number variation and TP53 mutation status were assessed in a subset of cases (<jats:italic>n<\/jats:italic>\u2009=\u200958).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CD3+ lymphocytes were the predominant cell subtype in the pure DCIS cohort, while FOXP3 showed the lowest levels. PDL1 expression was mainly seen in the stromal TILs. Higher abundance of TILs subtypes was associated with higher tumour grade, hormone receptor negativity and HER2 positivity. Mutant TP53 variants were associated with higher levels of stromal CD3+, CD4+ and FOXP3+ cells. DCIS coexisting with invasive carcinoma harboured denser stromal infiltrates of all immune cells and checkpoint proteins apart from CD4+ cells. Stromal PD1 was the most differentially expressed protein between DCIS and invasive carcinoma (<jats:italic>Z<\/jats:italic>\u2009=\u20095.8,<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Dense TILs, stromal FOXP3 and PDL1 were poor prognostic factors for DCIS recurrence, while dense TILs were independently associated with poor outcome for all recurrences (HR\u2009=\u20097.0;<jats:italic>p<\/jats:italic>\u2009=\u20090.024), and invasive recurrence (HR\u2009=\u20092.1;<jats:italic>p<\/jats:italic>\u2009=\u20090.029).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Immunosuppressive proteins are potential markers for high risk DCIS and disease progression. Different stromal and intratumoural lymphocyte composition between pure DCIS, DCIS associated with IBC and invasive carcinoma play a potential role in their prognostic significance and related to the underlying genomic instability. Assessment of overall TILs provides a promising tool for evaluation of the DCIS immune microenvironment.<\/jats:p><\/jats:sec>","DOI":"10.1038\/s41416-020-0797-7","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:06:05Z","timestamp":1584403565000},"page":"1496-1506","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["The prognostic significance of immune microenvironment in breast ductal carcinoma in situ"],"prefix":"10.1038","volume":"122","author":[{"given":"Michael S.","family":"Toss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asima","family":"Abidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothea","family":"Lesche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitra","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakshi","family":"Mahale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Saunders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanjina","family":"Kader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Islam M.","family":"Miligy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0488-5913","authenticated-orcid":false,"given":"Andrew R.","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylie L.","family":"Gorringe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emad A.","family":"Rakha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,17]]},"reference":[{"key":"797_CR1","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1093\/jnci\/94.20.1546","volume":"94","author":"VL Ernster","year":"2002","unstructured":"Ernster, V. L., Ballard-Barbash, R., Barlow, W. E., Zheng, Y., Weaver, D. L., Cutter, G. et al. Detection of ductal carcinoma in situ in women undergoing screening mammography. J. Natl Cancer Inst. 94, 1546\u20131554 (2002).","journal-title":"J. Natl Cancer Inst."},{"key":"797_CR2","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.breast.2016.09.001","volume":"31","author":"EJ Groen","year":"2017","unstructured":"Groen, E. J., Elshof, L. E., Visser, L. L., Th, E. J., Winter-warnars, H. A. O., Lips, E. H. et al. Finding the balance between over- and under-treatment of ductal carcinoma in situ (DCIS). Breast 31, 274\u2013283 (2017).","journal-title":"Breast"},{"key":"797_CR3","doi-asserted-by":"publisher","first-page":"4","DOI":"10.4161\/cbt.13.1.18869","volume":"13","author":"A Artacho-Cord\u00f3n","year":"2012","unstructured":"Artacho-Cord\u00f3n, A., Artacho-Cord\u00f3n, F., R\u00edos-Arrabal, S., Calvente, I. & N\u00fa\u00f1ez, M. I. Tumor microenvironment and breast cancer progression: a complex scenario. Cancer Biol. Ther. 13, 4\u201335 (2012).","journal-title":"Cancer Biol. Ther."},{"key":"797_CR4","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1126\/science.1203486","volume":"331","author":"RD Schreiber","year":"2011","unstructured":"Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity\u2019s roles in cancer suppression and promotion. Science 331, 1565\u20131570 (2011).","journal-title":"Science"},{"key":"797_CR5","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1586\/era.12.147","volume":"12","author":"LA Emens","year":"2012","unstructured":"Emens, L. A. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Expert Rev. Anticancer Ther. 12, 1597\u20131611 (2012).","journal-title":"Expert Rev. Anticancer Ther."},{"key":"797_CR6","first-page":"785317","volume":"2013","author":"LD Cruz-merino","year":"2013","unstructured":"Cruz-merino, L. D., Barco-s\u00e1nchez, A., Carrasco, F. H., Fern\u00e1ndez, E. N., Ben\u00edtez, A. V., Molina, J. B. et al. New insights into the role of the immune microenvironment in breast carcinoma. Clin. Dev. Immunol. 2013, 785317 (2013).","journal-title":"Clin. Dev. Immunol."},{"key":"797_CR7","doi-asserted-by":"publisher","first-page":"4977","DOI":"10.4049\/jimmunol.1001323","volume":"185","author":"BH Nelson","year":"2010","unstructured":"Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977\u20134982 (2010).","journal-title":"J. Immunol."},{"key":"797_CR8","doi-asserted-by":"publisher","first-page":"5074","DOI":"10.18632\/oncotarget.6231","volume":"26","author":"V Kotoula","year":"2016","unstructured":"Kotoula, V., Chatzopoulos, K., Lakis, S. & Alexopoulou, Z. Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials. Oncotarget 26, 5074\u20135087 (2016).","journal-title":"Oncotarget"},{"key":"797_CR9","doi-asserted-by":"publisher","unstructured":"Garc\u00eda-mart\u00ednez E., Gil G. L., Benito A. C., Gonz\u00e1lez-billalabeitia E., Angeles M., Conesa V. et al. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. Breast Cancer Res. https:\/\/doi.org\/10.1186\/s13058-014-0488-5. (2014)","DOI":"10.1186\/s13058-014-0488-5"},{"key":"797_CR10","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1093\/annonc\/mdu112","volume":"25","author":"S Loi","year":"2014","unstructured":"Loi, S., Michiels, S., Salgado, R., Sirtaine, N., Jose, V., Fumagalli, D. et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann. Oncol. 25, 1544\u20131550 (2014).","journal-title":"Ann. Oncol."},{"key":"797_CR11","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1200\/JCO.2014.58.1967","volume":"33","author":"C Denkert","year":"2015","unstructured":"Denkert, C., von Minckwitz, G., Brase, J. C., Sinn, B. V., Gade, S., Kronenwett, R. et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J. Clin. Oncol. 33, 983\u2013991 (2015).","journal-title":"J. Clin. Oncol."},{"issue":"27","key":"797_CR12","doi-asserted-by":"publisher","first-page":"2959","DOI":"10.1200\/JCO.2013.55.0491","volume":"32","author":"S Adams","year":"2014","unstructured":"Adams, S., Gray, R. J., Demaria, S., Goldstein, L., Perez, E. A., Shulman, L. N. et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J. Clin. Oncol. 32(27), 2959\u20132966 (2014).","journal-title":"J. Clin. Oncol."},{"key":"797_CR13","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/s10549-014-3185-2","volume":"148","author":"EM Ibrahim","year":"2014","unstructured":"Ibrahim, E. M., Al-Foheidi, M. E., Al-Mansour, M. M. & Kazkaz, G. A. The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis. Breast Cancer Res. Treat. 148, 467\u2013476 (2014).","journal-title":"Breast Cancer Res. Treat."},{"key":"797_CR14","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1038\/s41379-018-0040-8","volume":"31","author":"MS Toss","year":"2018","unstructured":"Toss, M. S., Miligy, I., Al-Kawaz, A., Alsleem, M., Khout, H., Rida, P. C. et al. Prognostic significance of tumor-infiltrating lymphocytes in ductal carcinoma in situ of the breast. Mod. Pathol. 31, 1226\u20131236 (2018).","journal-title":"Mod. Pathol."},{"key":"797_CR15","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1093\/annonc\/mdw623","volume":"28","author":"G Pruneri","year":"2017","unstructured":"Pruneri, G., Lazzeroni, M., Bagnardi, V., Tiburzio, G. B., Rotmensz, N., DeCensi, A. et al. The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast. Ann. Oncol. 28, 321\u2013328 (2017).","journal-title":"Ann. Oncol."},{"key":"797_CR16","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/his.12188","volume":"63","author":"M Van Bockstal","year":"2013","unstructured":"Van Bockstal, M., Lambein, K., Gevaert, O., De Wever, O., Praet, M., Cocquyt, V. et al. Stromal architecture and periductal decorin are potential prognostic markers for ipsilateral locoregional recurrence in ductal carcinoma in situ of the breast. Histopathology 63, 520\u2013533 (2013).","journal-title":"Histopathology"},{"key":"797_CR17","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","volume":"192","author":"GJ Freeman","year":"2000","unstructured":"Freeman, G. J., Long Aj Fau - Iwai, Y., Iwai, Y., Fau - Bourque, K., Bourque, K., Fau - Chernova, T., Chernova, T., Fau - Nishimura, H., Nishimura, H., Fau - Fitz, L. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027\u20131034 (2000).","journal-title":"J. Exp. Med."},{"key":"797_CR18","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1084\/jem.20051776","volume":"203","author":"ME Keir","year":"2006","unstructured":"Keir, M. E., Liang, S. C., Guleria, I., Latchman, Y. E., Qipo, A., Albacker, L. A. et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med 203, 883\u2013895 (2006).","journal-title":"J. Exp. Med"},{"key":"797_CR19","doi-asserted-by":"publisher","first-page":"5023","DOI":"10.2147\/OTT.S105862","volume":"9","author":"X Wang","year":"2016","unstructured":"Wang, X., Teng, F., Kong, L. & Yu, J. PD-L1 expression in human cancers and its association with clinical outcomes. OncoTargets Ther. 9, 5023\u20135039 (2016).","journal-title":"OncoTargets Ther."},{"key":"797_CR20","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","volume":"366","author":"SL Topalian","year":"2012","unstructured":"Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443\u20132454 (2012).","journal-title":"N. Engl. J. Med."},{"key":"797_CR21","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1038\/s41379-018-0086-7","volume":"31","author":"IM Miligy","year":"2018","unstructured":"Miligy, I. M., Gorringe, K. L., Toss, M. S., Al-Kawaz, A. A., Simpson, P., Diez-Rodriguez, M. et al. Thioredoxin-interacting protein is an independent risk stratifier for breast ductal carcinoma in situ. Mod. Pathol. 31, 1807\u20131815 (2018).","journal-title":"Mod. Pathol."},{"key":"797_CR22","doi-asserted-by":"publisher","first-page":"15","DOI":"10.5858\/133.1.15","volume":"133","author":"SC Lester","year":"2009","unstructured":"Lester, S. C., Bose, S., Chen, Y. Y., Connolly, J. L., de Baca, M. E., Fitzgibbons, P. L. et al. Protocol for the examination of specimens from patients with ductal carcinoma in situ of the breast. Arch. Pathol. Lab Med. 133, 15\u201325 (2009).","journal-title":"Arch. Pathol. Lab Med."},{"key":"797_CR23","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1200\/JOP.777003","volume":"6","author":"ME Hammond","year":"2010","unstructured":"Hammond, M. E., Hayes, D. F., Wolff, A. C., Mangu, P. B. & Temin, S. American society of clinical oncology\/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J. Oncol. Pract. 6, 195\u2013197 (2010).","journal-title":"J. Oncol. Pract."},{"key":"797_CR24","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1136\/jclinpath-2014-202571","volume":"68","author":"EA Rakha","year":"2015","unstructured":"Rakha, E. A., Pinder, S. E., Bartlett, J. M., Ibrahim, M., Starczynski, J., Carder, P. J. et al. Updated UK recommendations for HER2 assessment in breast cancer. J. Clin. Pathol. 68, 93\u201399 (2015).","journal-title":"J. Clin. Pathol."},{"key":"797_CR25","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1093\/annonc\/mdr304","volume":"22","author":"A Goldhirsch","year":"2011","unstructured":"Goldhirsch, A., Wood, W. C., Coates, A. S., Gelber, R. D., Thurlimann, B. & Senn, H. J. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann. Oncol. 22, 1736\u20131747 (2011).","journal-title":"Ann. Oncol."},{"key":"797_CR26","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1111\/j.1365-2559.2005.02045.x","volume":"46","author":"R Bos","year":"2005","unstructured":"Bos, R., van Diest, P. J., de Jong, J. S., van der Groep, P., van der Valk, P. & van der Wall, E. Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 46, 31\u201336 (2005).","journal-title":"Histopathology"},{"key":"797_CR27","doi-asserted-by":"publisher","first-page":"e56055","DOI":"10.1371\/journal.pone.0056055","volume":"8","author":"P van der Groep","year":"2013","unstructured":"van der Groep, P., van Diest, P. J., Smolders, Y. H., Ausems, M. G., van der Luijt, R. B., Menko, F. H. et al. HIF-1alpha overexpression in ductal carcinoma in situ of the breast in BRCA1 and BRCA2 mutation carriers. PloS ONE 8, e56055 (2013).","journal-title":"PloS ONE"},{"key":"797_CR28","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s13073-016-0375-z","volume":"8","author":"T Kader","year":"2016","unstructured":"Kader, T., Goode, D. L., Wong, S. Q., Connaughton, J., Rowley, S. M., Devereux, L. et al. Copy number analysis by low coverage whole genome sequencing using ultra low-input DNA from formalin-fixed paraffin embedded tumor tissue. Genome Med. 8, 121\u2013121 (2016).","journal-title":"Genome Med."},{"key":"797_CR29","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/0471250953.bi1110s43","volume":"43","author":"GA Van der Auwera","year":"2013","unstructured":"Van der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., Del Angel, G., Levy-Moonshine, A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinforma. 43, 11\u201333 (2013).","journal-title":"Curr. Protoc. Bioinforma."},{"key":"797_CR30","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1038\/ng.3036","volume":"46","author":"A Rimmer","year":"2014","unstructured":"Rimmer, A., Phan, H., Mathieson, I., Iqbal, Z., Twigg, S. R. F., Wilkie, A. O. M. et al. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 46, 912\u2013918 (2014).","journal-title":"Nat. Genet."},{"key":"797_CR31","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1101\/gr.129684.111","volume":"22","author":"DC Koboldt","year":"2012","unstructured":"Koboldt, D. C., Zhang, Q., Larson, D. E., Shen, D., McLellan, M. D., Lin, L. et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 22, 568\u2013576 (2012).","journal-title":"Genome Res."},{"key":"797_CR32","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren, W., Gil, L., Hunt, S. E., Riat, H. S., Ritchie, G. R., Thormann, A. et al. The ensembl variant effect predictor. Genome Bio. 17, 122 (2016).","journal-title":"Genome Bio."},{"key":"797_CR33","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285\u2013291 (2016).","journal-title":"Nature"},{"key":"797_CR34","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"A Auton","year":"2015","unstructured":"Auton, A., Brooks, L. D., Durbin, R. M., Garrison, E. P., Kang, H. M., Korbel, J. O. et al. A global reference for human genetic variation. Nature 526, 68\u201374 (2015).","journal-title":"Nature"},{"key":"797_CR35","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1101\/gr.175141.114","volume":"24","author":"I Scheinin","year":"2014","unstructured":"Scheinin, I., Sie, D., Bengtsson, H., van de Wiel, M. A., Olshen, A. B., van Thuijl, H. F. et al. DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly. Genome Res. 24, 2022\u20132032 (2014).","journal-title":"Genome Res."},{"key":"797_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0617-1","volume":"16","author":"T Kuilman","year":"2015","unstructured":"Kuilman, T., Velds, A., Kemper, K., Ranzani, M., Bombardelli, L., Hoogstraat, M. et al. CopywriteR: DNA copy number detection from off-target sequence data. Genome Biol. 16, 49 (2015).","journal-title":"Genome Biol."},{"key":"797_CR37","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1093\/bioinformatics\/btr670","volume":"28","author":"V Boeva","year":"2012","unstructured":"Boeva, V., Popova, T., Bleakley, K., Chiche, P., Cappo, J., Schleiermacher, G. et al. Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data. Bioinformatics 28, 423\u2013425 (2012).","journal-title":"Bioinformatics"},{"key":"797_CR38","first-page":"361","volume":"140","author":"AS Rathore","year":"2014","unstructured":"Rathore, A. S., Kumar, S., Konwar, R., Makker, A., Negi, M. P. & Goel, M. M. CD3+, CD4+ & CD8+ tumour infiltrating lymphocytes (TILs) are predictors of favourable survival outcome in infiltrating ductal carcinoma of breast. Indian J. Med. Res. 140, 361\u2013369 (2014).","journal-title":"Indian J. Med. Res."},{"key":"797_CR39","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s10549-016-4036-0","volume":"161","author":"MJ Campbell","year":"2017","unstructured":"Campbell, M. J., Baehner, F., O\u2019Meara, T., Ojukwu, E., Han, B., Mukhtar, R. et al. Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast. Breast Cancer Res. Treat. 161, 17\u201328 (2017).","journal-title":"Breast Cancer Res. Treat."},{"key":"797_CR40","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.breast.2016.02.014","volume":"27","author":"SC Doebar","year":"2016","unstructured":"Doebar, S. C., de Monye, C., Stoop, H., Rothbarth, J., Willemsen, S. P. & van Deurzen, C. H. Ductal carcinoma in situ diagnosed by breast needle biopsy: Predictors of invasion in the excision specimen. Breast 27, 15\u201321 (2016).","journal-title":"Breast"},{"key":"797_CR41","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1007\/s00428-004-1143-9","volume":"446","author":"H Kuroda","year":"2005","unstructured":"Kuroda, H., Tamaru J-i, Sakamoto, G., Ohnisi, K. & Itoyama, S. Immunophenotype of lymphocytic infiltration in medullary carcinoma of the breast. Virchows Arch. 446, 10\u201314 (2005).","journal-title":"Virchows Arch."},{"key":"797_CR42","doi-asserted-by":"publisher","unstructured":"Iseki Y., Shibutani M., Maeda K., Nagahara H. A new method for evaluating tumor- infiltrating lymphocytes (TILs) in colorectal cancer using hematoxylin and eosin (H-E)\u2014stained tumor sections. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0192744. (2018)","DOI":"10.1371\/journal.pone.0192744"},{"key":"797_CR43","first-page":"2445","volume":"29","author":"R Matkowski","year":"2009","unstructured":"Matkowski, R., Gisterek, I., Halon, A., Lacko, A., Szewczyk, K., Staszek, U. et al. The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer Res. 29, 2445\u20132451 (2009).","journal-title":"Anticancer Res."},{"key":"797_CR44","doi-asserted-by":"publisher","first-page":"2802","DOI":"10.1073\/pnas.1108781108","volume":"109","author":"VN Kristensen","year":"2012","unstructured":"Kristensen, V. N., Vaske, C. J., Ursini-Siegel, J., Van Loo, P., Nordgard, S. H., Sachidanandam, R. et al. Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling. Proc. Natl Acad. Sci. USA 109, 2802\u20132807 (2012).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"797_CR45","doi-asserted-by":"publisher","unstructured":"Miligy I., Mohan P., Gaber A., Aleskandarany M. A., Nolan C. C., Diez-rodriguez M. et al. Prognostic significance of tumour infiltrating B lymphocytes in breast ductal carcinoma in situ. Histopathology. https:\/\/doi.org\/10.1111\/his.13217. (2017)","DOI":"10.1111\/his.13217"},{"key":"797_CR46","doi-asserted-by":"publisher","unstructured":"Mahmoud S. M. A., Paish E. C., Lee A. H. S., Ellis I. O., Green A. R. An evaluation of the clinical significance of FOXP3 + infiltrating cells in human breast cancer. Breast Cancer Res. Treat. https:\/\/doi.org\/10.1007\/s10549-010-0987-8. (2011)","DOI":"10.1007\/s10549-010-0987-8"},{"key":"797_CR47","doi-asserted-by":"publisher","first-page":"5373","DOI":"10.1200\/JCO.2006.05.9584","volume":"24","author":"GJ Bates","year":"2018","unstructured":"Bates, G. J., Fox, S. B., Han, C., Leek, R. D., Garcia, J. F., Harris, A. L. et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 24, 5373\u20135380 (2018).","journal-title":"J. Clin. Oncol."},{"key":"797_CR48","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1007\/s10549-013-2556-4","volume":"139","author":"A Lal","year":"2013","unstructured":"Lal A., Chan L., Devries S., Chin K., Scott G. K., Benz C. C. et al. FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast. Breast Cancer Res. Treat. 139, 381\u2013390. (2013).","journal-title":"Breast Cancer Res. Treat"},{"key":"797_CR49","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1158\/2159-8290.CD-17-0222","volume":"7","author":"CR Gil Del Alcazar","year":"2017","unstructured":"Gil Del Alcazar, C. R., Huh, S. J., Ekram, M. B., Trinh, A., Liu, L. L., Beca, F. et al. Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Disco. 7, 1098\u20131115 (2017).","journal-title":"Cancer Disco."},{"key":"797_CR50","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s10549-019-05272-2","volume":"177","author":"XY Chen","year":"2019","unstructured":"Chen, X. Y., Yeong, J., Thike, A. A., Bay, B. H. & Tan, P. H. Prognostic role of immune infiltrates in breast ductal carcinoma in situ. Breast Cancer Res. Treat. 177, 17\u201327 (2019).","journal-title":"Breast Cancer Res. Treat."},{"key":"797_CR51","doi-asserted-by":"publisher","unstructured":"Merlo A., Casalini P., Carcangiu M. L., Malventano C., Triulzi T., Me S. FOXP3 Expression and overall survival in breast cancer. J. Clin. Oncol. https:\/\/doi.org\/10.1200\/JCO.2008.17.9036. (2018)","DOI":"10.1200\/JCO.2008.17.9036"},{"key":"797_CR52","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/nm1093","volume":"10","author":"TJ Curiel","year":"2004","unstructured":"Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942\u2013949 (2004).","journal-title":"Nat. Med."},{"key":"797_CR53","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/jcp.27172","volume":"234","author":"FK Dermani","year":"2019","unstructured":"Dermani, F. K., Samadi, P., Rahmani, G., Kohlan, A. K. & Najafi, R. PD-1\/PD-L1 immune checkpoint: potential target for cancer therapy. J. Cell Physiol. 234, 1313\u20131325 (2019).","journal-title":"J. Cell Physiol."},{"key":"797_CR54","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.1158\/1078-0432.CCR-06-2746","volume":"13","author":"T Nomi","year":"2007","unstructured":"Nomi, T., Sho, M., Akahori, T., Hamada, K., Kubo, A., Kanehiro, H. et al. Clinical Significance and therapeutic potential of the programmed death-1 ligand\/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13, 2151 (2007).","journal-title":"Clin. Cancer Res."},{"key":"797_CR55","doi-asserted-by":"publisher","first-page":"17174","DOI":"10.1073\/pnas.0406351101","volume":"101","author":"RH Thompson","year":"2004","unstructured":"Thompson, R. H., Gillett, Md, Cheville, J. C., Lohse, C. M., Dong, H., Webster, W. S. et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl Acad. Sci. USA 101, 17174\u201317179 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"797_CR56","doi-asserted-by":"publisher","unstructured":"Trella E., Droeser R. A., Muenst S., Schaerli A. R., Gao F., Muraro M. G. et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res. Treat. https:\/\/doi.org\/10.1007\/s10549-014-2988-5. (2014)","DOI":"10.1007\/s10549-014-2988-5"},{"key":"797_CR57","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1158\/1078-0432.CCR-06-2599","volume":"15","author":"RH Thompson","year":"2007","unstructured":"Thompson, R. H., Dong, H., Lohse, C. M., Leibovich, B. C., Blute, M. L., Cheville, J. C. et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin. Cancer Res. 15, 1757\u20131761 (2007).","journal-title":"Clin. Cancer Res."},{"key":"797_CR58","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1007\/s10549-013-2581-3","volume":"139","author":"S Muenst","year":"2013","unstructured":"Muenst, S., Soysal, S. D., Gao, F., Obermann, E. C., Oertli, D. & EGillanders, W. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res. Treat. 139, 667\u2013676 (2013).","journal-title":"Breast Cancer Res. Treat."},{"key":"797_CR59","doi-asserted-by":"publisher","unstructured":"Schalper K. A., Velcheti V., Carvajal D., Wimberly H., Brown J., Pusztai L. et al. In Situ Tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin. Cancer Res. https:\/\/doi.org\/10.1158\/1078-0432.CCR-13-2702. (2014)","DOI":"10.1158\/1078-0432.CCR-13-2702"},{"key":"797_CR60","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1158\/2326-6066.CIR-13-0127","volume":"2","author":"EA Mittendorf","year":"2014","unstructured":"Mittendorf, E. A., Philips, A. V., Meric-Bernstam, F., Qiao, N., Wu, Y., Harrington, S. et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol. Res 2, 361\u2013370 (2014).","journal-title":"Cancer Immunol. Res"},{"key":"797_CR61","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.yexcr.2004.08.037","volume":"301","author":"YG Man","year":"2004","unstructured":"Man, Y. G. & Sang, Q. X. The significance of focal myoepithelial cell layer disruptions in human breast tumor invasion: a paradigm shift from the \u201cprotease-centered\u201d hypothesis. Exp. Cell Res. 301, 103\u2013118 (2004).","journal-title":"Exp. Cell Res."},{"key":"797_CR62","doi-asserted-by":"publisher","first-page":"84","DOI":"10.7150\/jca.5482","volume":"4","author":"YG Man","year":"2013","unstructured":"Man, Y. G., Stojadinovic, A., Mason, J., Avital, I., Bilchik, A., Bruecher, B. et al. Tumor-infiltrating immune cells promoting tumor invasion and metastasis: existing theories. J. Cancer 4, 84\u201395 (2013).","journal-title":"J. Cancer"},{"key":"797_CR63","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/modpathol.2015.158","volume":"29","author":"E Thompson","year":"2016","unstructured":"Thompson, E., Taube, J. M., Elwood, H., Sharma, R., Meeker, A., Warzecha, H. N. et al. The immune microenvironment of breast ductal carcinoma in situ. Mod. Pathol. 29, 249\u2013258 (2016).","journal-title":"Mod. Pathol."},{"key":"797_CR64","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2222","volume":"11","author":"X-J Ma","year":"2009","unstructured":"Ma, X.-J., Dahiya, S., Richardson, E., Erlander, M. & Sgroi, D. C. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res. 11, R7 (2009).","journal-title":"Breast Cancer Res."},{"key":"797_CR65","doi-asserted-by":"publisher","first-page":"5449","DOI":"10.18632\/oncotarget.3216","volume":"6","author":"R Sabatier","year":"2015","unstructured":"Sabatier, R., Finetti, P., Mamessier, E., Adelaide, J., Chaffanet, M., Ali, H. R. et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6, 5449\u20135464 (2015).","journal-title":"Oncotarget"},{"key":"797_CR66","doi-asserted-by":"publisher","first-page":"3689","DOI":"10.1172\/JCI84430","volume":"126","author":"D Triner","year":"2016","unstructured":"Triner, D. & Shah, Y. M. Hypoxia-inducible factors: a central link between inflammation and cancer. J. Clin. Invest. 126, 3689\u20133698 (2016).","journal-title":"J. Clin. Invest."},{"key":"797_CR67","first-page":"7","volume":"22","author":"S Chouaib","year":"2018","unstructured":"Chouaib, S., Umansky, V. & Kieda, C. The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment. Contemp. Oncol. (Pozn.) 22, 7\u201313 (2018).","journal-title":"Contemp. Oncol. (Pozn.)"},{"key":"797_CR68","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/nri1685","volume":"5","author":"M Sitkovsky","year":"2005","unstructured":"Sitkovsky, M. & Lukashev, D. Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat. Rev. Immunol. 5, 712\u2013721 (2005).","journal-title":"Nat. Rev. Immunol."},{"key":"797_CR69","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1038\/modpathol.2015.79","volume":"28","author":"A Knopfelmacher","year":"2015","unstructured":"Knopfelmacher, A., Fox, J., Lo, Y., Shapiro, N. & Fineberg, S. Correlation of histopathologic features of ductal carcinoma in situ of the breast with the oncotype DX DCIS score. Mod. Pathol. 28, 1167\u20131173 (2015).","journal-title":"Mod. Pathol."},{"key":"797_CR70","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1016\/j.cell.2017.08.028","volume":"170","author":"ER Kastenhuber","year":"2017","unstructured":"Kastenhuber, E. R. & Lowe, S. W. Putting p53 in Context. Cell 170, 1062\u20131078 (2017).","journal-title":"Cell"}],"container-title":["British Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-0797-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-0797-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-0797-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T07:30:39Z","timestamp":1722583839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-0797-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,17]]},"references-count":70,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2020,5,12]]}},"alternative-id":["797"],"URL":"https:\/\/doi.org\/10.1038\/s41416-020-0797-7","relation":{},"ISSN":["0007-0920","1532-1827"],"issn-type":[{"value":"0007-0920","type":"print"},{"value":"1532-1827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,17]]},"assertion":[{"value":"15 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 February 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 March 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This work obtained ethics approval by the North West \u2013 Greater Manchester Central Research Ethics Committee under the title; Nottingham Health Science Biobank (NHSB), reference number 15\/NW\/0685. All patients included in this study were consented to participate in the study and to use their materials in research. All samples from Nottingham used in this study were pseudo-anonymised and stored in compliance with the UK Human Tissue Act. The study was performed in accordance with the Declaration of Helsinki.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors confirm the data that has been used in this work is available on reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This research was supported and funded by the Egyptian Ministry of Higher Education and Scientific Research. This research was supported by the Peter MacCallum Cancer Foundation and by the National Breast Cancer Foundations (IIRS-18-051).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding information"}}]}}