{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:22:26Z","timestamp":1793823746407,"version":"4.6.1"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T00:00:00Z","timestamp":1581465600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T00:00:00Z","timestamp":1581465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100011010","name":"Stichting Zabawas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","award":["OT123-361"],"award-info":[{"award-number":["OT123-361"]}],"id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Objectives<\/jats:title>\n<jats:p>A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8<jats:sup>+<\/jats:sup> T cell infiltration, HLA class-I and PD-L1 expression in the tumor.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>Metastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in FFPE tissue for TML (NGS: 409 cancer-related-genes) and by IHC staining to score PD-L1, CD8<jats:sup>+<\/jats:sup> T cell infiltration, HLA class-I. PFS (RECISTv1.1) and OS were analyzed by Kaplan\u2013Meier methodology.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%) were included. High TML was associated with better PFS (<jats:italic>p<\/jats:italic>\u2009=\u20090.004) and OS (<jats:italic>p<\/jats:italic>\u2009=\u20090.025). Interaction analyses revealed that patients with both high TML and high total CD8<jats:sup>+<\/jats:sup> T cell infiltrate (<jats:italic>p<\/jats:italic>\u2009=\u20090.023) or no loss of HLA class-I (<jats:italic>p<\/jats:italic>\u2009=\u20090.026), patients with high total CD8<jats:sup>+<\/jats:sup> T cell infiltrate and no loss of HLA class-I (<jats:italic>p<\/jats:italic>\u2009=\u20090.041) or patients with both high PD-L1 and high TML (<jats:italic>p<\/jats:italic>\u2009=\u20090.003) or no loss of HLA class-I (<jats:italic>p<\/jats:italic>\u2009=\u20090.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (<jats:italic>p<\/jats:italic>\u2009=\u20090.007).<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8<jats:sup>+<\/jats:sup> T cell infiltration and HLA class-I functions as a better predictive biomarker for response to anti-PD-1 immunotherapy. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.<\/jats:p>\n<\/jats:sec>","DOI":"10.1007\/s00262-020-02506-x","type":"journal-article","created":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T03:03:55Z","timestamp":1581476635000},"page":"771-777","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Tumor mutational load, CD8+ T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8750-5188","authenticated-orcid":false,"given":"Daan P.","family":"Hurkmans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merian E.","family":"Kuipers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Smit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"van Marion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron H. J.","family":"Mathijssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet E.","family":"Postmus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter S.","family":"Hiemstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim G. J. V.","family":"Aerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H.","family":"von der Th\u00fcsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sjoerd H.","family":"van der Burg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,12]]},"reference":[{"key":"2506_CR1","first-page":"41","volume":"475","author":"D Hurkmans","year":"2019","unstructured":"Hurkmans D, Kuipers M, Smit J et al (2019) Combined assessment of tumour mutational load, CD8+ T cell infiltration, and expression of PD-L1 and HLA class I in small biopsy specimens to predict immunotherapy response in non-small cell lung cancer. Virchows Arch. 475:41 (OFP-10-008 Oral presentation)","journal-title":"Virchows Arch."},{"key":"2506_CR2","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/j.jtho.2019.08.1552","volume":"14","author":"D Hurkmans","year":"2019","unstructured":"Hurkmans D, Kuipers M, Smit J et al (2019) Tumor mutational load, CD8+ T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions. J Thoracic Oncol. 14:726 (P2.04-47 Poster abstract)","journal-title":"J Thoracic Oncol."},{"key":"2506_CR3","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1001\/jamaoncol.2016.0639","volume":"2","author":"AG Sacher","year":"2016","unstructured":"Sacher AG, Gandhi L (2016) Biomarkers for the clinical use of PD-1\/PD-L1 Inhibitors in non-small-cell lung cancer: a review. JAMA Oncol 2:1217\u20131222. https:\/\/doi.org\/10.1001\/jamaoncol.2016.0639","journal-title":"JAMA Oncol"},{"key":"2506_CR4","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nrc.2016.36","volume":"16","author":"SL Topalian","year":"2016","unstructured":"Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275\u2013287. https:\/\/doi.org\/10.1038\/nrc.2016.36","journal-title":"Nat Rev Cancer"},{"key":"2506_CR5","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jtho.2017.11.123","volume":"13","author":"D Fujimoto","year":"2018","unstructured":"Fujimoto D, Sato Y, Uehara K et al (2018) Predictive performance of four programmed cell death ligand 1 assay systems on nivolumab response in previously treated patients with non-small cell lung cancer. J Thorac Oncol 13:377\u2013386. https:\/\/doi.org\/10.1016\/j.jtho.2017.11.123","journal-title":"J Thorac Oncol"},{"key":"2506_CR6","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1126\/science.aaa1348","volume":"348","author":"NA Rizvi","year":"2015","unstructured":"Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124\u2013128. https:\/\/doi.org\/10.1126\/science.aaa1348","journal-title":"Science"},{"key":"2506_CR7","doi-asserted-by":"publisher","first-page":"616","DOI":"10.21037\/tlcr.2018.08.01","volume":"7","author":"R Chaudhary","year":"2018","unstructured":"Chaudhary R, Quagliata L, Martin JP et al (2018) A scalable solution for tumor mutational burden from formalin-fixed, paraffin-embedded samples using the oncomine tumor mutation load assay. Transl Lung Cancer Res 7:616\u2013630. https:\/\/doi.org\/10.21037\/tlcr.2018.08.01","journal-title":"Transl Lung Cancer Res"},{"key":"2506_CR8","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s00262-007-0362-8","volume":"57","author":"AM Mehta","year":"2008","unstructured":"Mehta AM, Jordanova ES, Kenter GG, Ferrone S, Fleuren GJ (2008) Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma. Cancer Immunol Immunother 57:197\u2013206. https:\/\/doi.org\/10.1007\/s00262-007-0362-8","journal-title":"Cancer Immunol Immunother"},{"issue":"1259\u201371","key":"2506_CR9","doi-asserted-by":"publisher","first-page":"e11","DOI":"10.1016\/j.cell.2017.10.001","volume":"171","author":"N McGranahan","year":"2017","unstructured":"McGranahan N, Rosenthal R, Hiley CT et al (2017) Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. Cell 171(1259\u201371):e11. https:\/\/doi.org\/10.1016\/j.cell.2017.10.001","journal-title":"Cell"},{"key":"2506_CR10","doi-asserted-by":"publisher","first-page":"3477","DOI":"10.18632\/oncotarget.6506","volume":"7","author":"M Talebian Yazdi","year":"2016","unstructured":"Talebian Yazdi M, van Riet S, van Schadewijk A, Fiocco M, van Hall T, Taube C, Hiemstra PS, van der Burg SH (2016) The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma. Oncotarget 7:3477\u20133488. https:\/\/doi.org\/10.18632\/oncotarget.6506","journal-title":"Oncotarget"},{"key":"2506_CR11","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1126\/science.aao4572","volume":"359","author":"D Chowell","year":"2018","unstructured":"Chowell D, Morris LGT, Grigg CM et al (2018) Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359:582\u2013587. https:\/\/doi.org\/10.1126\/science.aao4572","journal-title":"Science"},{"key":"2506_CR12","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1016\/S0959-8049(98)00151-8","volume":"34","author":"DJ Ruiter","year":"1998","unstructured":"Ruiter DJ, Ferrier CM, van Muijen GN, Henzen-Logmans SC, Kennedy S, Kramer MD, Nielsen BS, Schmitt M (1998) Quality control of immunohistochemical evaluation of tumour-associated plasminogen activators and related components. European BIOMED-1 concerted action on clinical relevance of proteases in tumour invasion and metastasis. Eur J Cancer 34:1334\u20131340","journal-title":"Eur J Cancer"},{"key":"2506_CR13","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12865-018-0285-5","volume":"20","author":"X Wang","year":"2019","unstructured":"Wang X, Li M (2019) Correlate tumor mutation burden with immune signatures in human cancers. BMC Immunol 20:4. https:\/\/doi.org\/10.1186\/s12865-018-0285-5","journal-title":"BMC Immunol"},{"key":"2506_CR14","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/s41586-019-1032-7","volume":"567","author":"R Rosenthal","year":"2019","unstructured":"Rosenthal R, Cadieux EL, Salgado R et al (2019) Neoantigen-directed immune escape in lung cancer evolution. Nature 567:479\u2013485. https:\/\/doi.org\/10.1038\/s41586-019-1032-7","journal-title":"Nature"},{"key":"2506_CR15","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.cell.2017.04.004","volume":"169","author":"MD Buck","year":"2017","unstructured":"Buck MD, Sowell RT, Kaech SM, Pearce EL (2017) Metabolic instruction of immunity. Cell 169:570\u2013586. https:\/\/doi.org\/10.1016\/j.cell.2017.04.004","journal-title":"Cell"},{"key":"2506_CR16","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1038\/s41591-018-0134-3","volume":"24","author":"DR Gandara","year":"2018","unstructured":"Gandara DR, Paul SM, Kowanetz M et al (2018) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24:1441\u20131448. https:\/\/doi.org\/10.1038\/s41591-018-0134-3","journal-title":"Nat Med"},{"key":"2506_CR17","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.3892\/ol.2015.3471","volume":"10","author":"X Li","year":"2015","unstructured":"Li X, Guo F, Liu Y et al (2015) NLRC5 expression in tumors and its role as a negative prognostic indicator in stage III non-small-cell lung cancer patients. Oncol Lett 10:1533\u20131540. https:\/\/doi.org\/10.3892\/ol.2015.3471","journal-title":"Oncol Lett"},{"key":"2506_CR18","doi-asserted-by":"publisher","first-page":"5097","DOI":"10.1038\/s41467-018-07603-1","volume":"9","author":"A Durgeau","year":"2018","unstructured":"Durgeau A, Virk Y, Gros G et al (2018) Human preprocalcitonin self-antigen generates TAP-dependent and -independent epitopes triggering optimised T-cell responses toward immune-escaped tumours. Nat Commun 9:5097. https:\/\/doi.org\/10.1038\/s41467-018-07603-1","journal-title":"Nat Commun"},{"key":"2506_CR19","doi-asserted-by":"publisher","first-page":"1599639","DOI":"10.1080\/2162402X.2019.1599639","volume":"8","author":"KA Marijt","year":"2019","unstructured":"Marijt KA, Van Der Burg SH, van Hall T (2019) TEIPP peptides: exploration of unTAPped cancer antigens. Oncoimmunology 8:1599639. https:\/\/doi.org\/10.1080\/2162402X.2019.1599639","journal-title":"Oncoimmunology"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-020-02506-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00262-020-02506-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-020-02506-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T13:14:42Z","timestamp":1613049282000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00262-020-02506-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,12]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["2506"],"URL":"https:\/\/doi.org\/10.1007\/s00262-020-02506-x","relation":{},"ISSN":["0340-7004","1432-0851"],"issn-type":[{"value":"0340-7004","type":"print"},{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,12]]},"assertion":[{"value":"27 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 January 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"J.G.J.V. Aerts and P.E. Postmus have an advisory role for Bristol-Myers Squibb, J.H. von der Th\u00fcsen received research funding from Bristol-Myers Squibb. The authors declare that there are no other conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Trial number and trial registration details: MULTOMAB trial, Dutch Trial Register number NTR7015\/ NL6828, ethics approval by responsible authority Medical Research Ethics Committee Erasmus MC, reference number: 16-011. The use of archival FFPE samples was in accordance with guidelines from the Dutch Federation of Medical Research and was approved by responsible authority Medical Research Ethics Committee Erasmus MC, reference number: 17-1186.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and ethical standards"}},{"value":"All patients signed written informed consent to use data and materials for research and publication, which was provided before study entry (MULTOMAB trial, NTR7015\/NL6828).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}