{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:25:16Z","timestamp":1791645916775,"version":"4.3.4"},"reference-count":46,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"unspecified","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"UVA School of Medicine Summer Medical Research Internship Program","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Collaborative Research Award from the UVA Beirne Carter Center for Immunology Research","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"UVA College Science Scholars Summer Research stipend","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"UVA Comprehensive Cancer Center Support Grant, NIH NCI","award":["P30CA044579"],"award-info":[{"award-number":["P30CA044579"]}]},{"name":"Cancer Team Science Award from the UVA Comprehensive Cancer Center","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM145443"],"award-info":[{"award-number":["T32 GM145443"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32 CA163177"],"award-info":[{"award-number":["T32 CA163177"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,8,13]]},"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFN\u03b3-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single-cell neighborhoods from mIF images followed by multivariate discriminant analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Spatial quantitation of tumor cell MHC-I expression revealed intratumoral and intertumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56\n                      <jats:sup>+<\/jats:sup>\n                      cell numbers in patient tumors were positively associated with disease-free survival (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      cells (HR=0.199, p&lt;1\u00d710\n                      <jats:sup>\u22123<\/jats:sup>\n                      ). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and CD3\n                      <jats:sup>\u2013<\/jats:sup>\n                      CD56\n                      <jats:sup>+<\/jats:sup>\n                      NK cells in MHC-I-bearing tumors (p&lt;0.05). To infer associations of functional cell states and local cell\u2013cell communication, we analyzed spatial single-cell neighborhood profiles to delineate the cellular environments of IFN\u03b3\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                      NK cells and T cells. We discovered that both IFN\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      NK and CD8 T cells were more frequently associated with other IFN\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      lymphocytes in comparison to IFN\u03b3\n                      <jats:sup>\u2013<\/jats:sup>\n                      NK cells and CD8 T cells (p&lt;1\u00d710\n                      <jats:sup>\u201330<\/jats:sup>\n                      ). Moreover, IFN\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      lymphocytes were most often found clustered near MHC-I\n                      <jats:sup>+<\/jats:sup>\n                      tumor cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Coassociation of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFN\u03b3. Frequent colocalization of IFN\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      NK cells with other IFN\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-009126","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T03:10:19Z","timestamp":1726715419000},"page":"e009126","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8596-4700","authenticated-orcid":false,"given":"Remziye E","family":"Wessel","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nardin","family":"Ageeb","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6111-9289","authenticated-orcid":false,"given":"Joseph M","family":"Obeid","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Temple University Hospital, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana S","family":"Mauldin","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate A","family":"Goundry","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0202-062X","authenticated-orcid":false,"given":"Gabriel F","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdin","family":"Hossain","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Lehman","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8983-6677","authenticated-orcid":false,"given":"Ryan D","family":"Gentzler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology and Oncology, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan A","family":"Wages","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6664-4373","authenticated-orcid":false,"suffix":"Jr","given":"Craig L","family":"Slingluff","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6141-3261","authenticated-orcid":false,"given":"Timothy N J","family":"Bullock","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA"},{"name":"Department of Pathology, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-0933","authenticated-orcid":false,"given":"Sepideh","family":"Dolatshahi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA"},{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2872-7685","authenticated-orcid":false,"given":"Michael G","family":"Brown","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA"},{"name":"Department of Medicine, Nephrology Division, University of Virginia, Charlottesville, Virginia, USA"},{"name":"Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA"},{"name":"Department of Microbiology, Immunology and Cancer Biology, Univesity of Virginia, School of Medicine, Charlottesville, Virginia, 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