{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T03:51:27Z","timestamp":1773719487442,"version":"3.50.1"},"reference-count":41,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T00:00:00Z","timestamp":1678665600000},"content-version":"unspecified","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"the National Institutes of Health, National Center for Advancing Translational Sciences","award":["UL1TR002529"],"award-info":[{"award-number":["UL1TR002529"]}]},{"name":"NIH","award":["CA225108"],"award-info":[{"award-number":["CA225108"]}]},{"name":"NCI","award":["P30CA082709"],"award-info":[{"award-number":["P30CA082709"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,2,20]]},"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells in tumor microenvironment, which suppress antitumor immunity. Expansion of various MDSC subpopulations is closely associated with poor clinical outcomes in cancer. Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) in mice induces the differentiation of myeloid lineage cells into MDSCs. These <jats:italic>Lal<\/jats:italic>\n                     <jats:sup>-\/-<\/jats:sup> MDSCs not only suppress immune surveillance but also stimulate cancer cell proliferation and invasion. Understanding and elucidating the underlying mechanisms of MDSCs biogenesis will help to facilitate diagnosis\/prognosis of cancer occurrence and prevent cancer growth and spreading.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Single-cell RNA sequencing (scRNA-seq) was performed to distinguish intrinsic molecular and cellular differences between normal versus <jats:italic>Lal<\/jats:italic>\n                     <jats:sup>-\/-<\/jats:sup> bone marrow\u2013derived Ly6G<jats:sup>+<\/jats:sup> myeloid populations in mice. In humans, LAL expression and metabolic pathways in various myeloid subsets of blood samples of patients with non-small cell lung cancer (NSCLC) were assessed by flow cytometry. The profiles of myeloid subsets were compared in patients with NSCLC before and after the treatment of programmed death-1 (PD-1) immunotherapy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>scRNA-seq of <jats:italic>Lal<\/jats:italic>\n                     <jats:sup>-\/-<\/jats:sup> CD11b<jats:sup>+<\/jats:sup>Ly6G<jats:sup>+<\/jats:sup> MDSCs identified two distinctive clusters with differential gene expression patterns and revealed a major metabolic shift towards glucose utilization and reactive oxygen species (ROS) overproduction. Blocking pyruvate dehydrogenase (PDH) in glycolysis reversed <jats:italic>Lal<\/jats:italic>\n                     <jats:sup>-\/-<\/jats:sup> MDSCs\u2019 capabilities of immunosuppression and tumor growth stimulation and reduced ROS overproduction. In the blood samples of human patients with NSCLC, LAL expression was significantly decreased in CD13<jats:sup>+<\/jats:sup>\/CD14<jats:sup>+<\/jats:sup>\/CD15<jats:sup>+<\/jats:sup>\/CD33<jats:sup>+<\/jats:sup> myeloid cell subsets. Further analysis in the blood of patients with NSCLC revealed an expansion of CD13<jats:sup>+<\/jats:sup>\/CD14<jats:sup>+<\/jats:sup>\/CD15<jats:sup>+<\/jats:sup> myeloid cell subsets, accompanied by upregulation of glucose-related and glutamine-related metabolic enzymes. Pharmacological inhibition of the LAL activity in the blood cells of healthy participants increased the numbers of CD13<jats:sup>+<\/jats:sup> and CD14<jats:sup>+<\/jats:sup> myeloid cell subsets. PD-1 checkpoint inhibitor treatment in patients with NSCLC reversed the increased number of CD13<jats:sup>+<\/jats:sup> and CD14<jats:sup>+<\/jats:sup> myeloid cell subsets and PDH levels in CD13<jats:sup>+<\/jats:sup> myeloid cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These results demonstrate that LAL and the associated expansion of MDSCs could serve as targets and biomarkers for anticancer immunotherapy in humans.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-006272","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T10:57:28Z","timestamp":1678705048000},"page":"e006272","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["LAL deficiency induced myeloid-derived suppressor cells as targets and biomarkers for lung 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shadia","family":"Jalal","sequence":"additional","affiliation":[{"name":"IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinchun","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, 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