{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:54:50Z","timestamp":1790963690724,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,7,18]],"date-time":"2020-07-18T00:00:00Z","timestamp":1595030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,7,18]],"date-time":"2020-07-18T00:00:00Z","timestamp":1595030400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF I 3522"],"award-info":[{"award-number":["FWF I 3522"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF I 3977"],"award-info":[{"award-number":["FWF I 3977"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["I4677"],"award-info":[{"award-number":["I4677"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:p>\n                    Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)\u2010high and NE\u2010low subtypes showing \u2018immune desert\u2019 and \u2018immune oasis\u2019 phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross\u2010sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early\u2010stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE\u2010associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin\u2010fixed paraffin\u2010embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3\u2010dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45\n                    <jats:sup>+<\/jats:sup>\n                    cell) density was significantly higher in tumor nests (\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0=\u00a00.019), with increased CD8\n                    <jats:sup>+<\/jats:sup>\n                    effector T\u2010cell infiltration (\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0=\u00a00.003) in NE\u2010low vs NE\u2010high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE\u2010low primary tumors (vs NE\u2010high,\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0&lt;\u00a00.05). We also found significantly higher MHC II expression by malignant cells in NE\u2010low (vs NE\u2010high,\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0=\u00a00.004) tumors. TIM3 expression was significantly increased in NE\u2010low (vs NE\u2010high,\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0&lt;\u00a00.05) tumors and in LN metastases (vs primary tumors,\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0&lt;\u00a00.05). To our knowledge, this is the first human study that demonstrates\n                    <jats:italic>in\u00a0situ<\/jats:italic>\n                    that NE\u2010low SCLCs are associated with increased immune cell infiltration compared to NE\u2010high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE\u2010low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.12741","type":"journal-article","created":{"date-parts":[[2020,6,7]],"date-time":"2020-06-07T10:51:11Z","timestamp":1591527071000},"page":"1947-1965","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-5701","authenticated-orcid":false,"given":"David","family":"Dora","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology and Embryology Faculty of Medicine Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Rivard","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Bunn","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Suda","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery Department of Surgery Faculty of Medicine Kindai University Osaka\u2010Sayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengxiang","family":"Ren","sequence":"additional","affiliation":[{"name":"Shanghai Pulmonary Hospital Tongji University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivaun","family":"Lueke Pickard","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Laszlo","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology Budapest Hungary"},{"name":"Department of Thoracic Surgery Semmelweis University and National Institute of Oncology Budapest Hungary"},{"name":"Division of Thoracic Surgery Department of Surgery Comprehensive Cancer Center Medical University of Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tunde","family":"Harko","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Megyesfalvi","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology Budapest Hungary"},{"name":"Department of Thoracic Surgery Semmelweis University and National Institute of Oncology Budapest Hungary"},{"name":"Division of Thoracic Surgery Department of Surgery Comprehensive Cancer Center Medical University of Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Moldvay","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred R.","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USA"},{"name":"Tisch Cancer Institute Center for Thoracic Oncology Mount Sinai Health System New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balazs","family":"Dome","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology Budapest Hungary"},{"name":"Department of Thoracic Surgery Semmelweis University and National Institute of Oncology Budapest Hungary"},{"name":"Division of Thoracic Surgery Department of Surgery Comprehensive Cancer Center Medical University of Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Lohinai","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology Budapest 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