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Adelson Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Rosalie and Harold Rae Brown Family Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Commun Signal"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immunotherapies such as immune checkpoint inhibitors (ICIs) targeting programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have successfully improved outcomes in metastatic melanoma (MM) patients. PD-L1 and major histocompatibility complex class II (MHC-II) levels in tumor cells are critical in modulating ICI responses; however, the regulatory mechanisms controlling PD-L1 and MHC-II expression levels are still not fully characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Targeted mRNA sequencing data comparing tissue samples from MM patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200925). Publicly available RNA-Seq [TCGA-SKCM (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009383), PMID31792460 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009121), PRJEB23709 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200973)] and proteomic [PXD006003 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200963)] datasets from MM patients were utilized for bioinformatic analysis. Functional assays were performed on MM cell lines and multiplex immunofluorescence on tumor samples from MM patients to validate in-silico observations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Here, we showed that interferon gamma (IFN-\u03b3) inducible factor 30 (IFI30) has a dual role in preventing PD-L1 and MHC-II lysosomal degradation mediated by cathepsin L (CTSL), and modulating IFN-\u03b3 pathway signaling. Briefly, IFI30, PD-L1, MHC-II and CTSL levels are stimulated by IFN-\u03b3 in MM cell lines. The basal and IFN-\u03b3-stimulated protein\/mRNA levels of PD-L1 and MHC-II dramatically decreased, while CTSL levels increased in MM with\n                      <jats:italic>IFI30<\/jats:italic>\n                      knockdown. Blockage of lysosome acidification prevented PD-L1 protein degradation in MM with\n                      <jats:italic>IFI30<\/jats:italic>\n                      knockdown. Conversely,\n                      <jats:italic>CTSL<\/jats:italic>\n                      knockdown significantly increased IFI30, PD-L1 and MHC-II levels.\n                      <jats:italic>IFI30<\/jats:italic>\n                      knockdown decreased the levels of IFN-\u03b3 receptor 1 (IFNGR1) at the plasma membrane, blocked IFN-\u03b3 pathway downstream signaling, and decreased PD-L1 and MHC-II mRNA\/protein levels.\n                      <jats:italic>IFNGR1<\/jats:italic>\n                      knockdown in MM cells resembled the phenotype observed for\n                      <jats:italic>IFI30<\/jats:italic>\n                      knockdown. Of clinical relevance, MM patients with high-\n                      <jats:italic>IFI30<\/jats:italic>\n                      levels in tumor tissue samples showed a better progression-free survival and better responses to ICIs in three independent datasets (PMID31792460, PRJEB23709, and PXD006003). High-\n                      <jats:italic>IFI30<\/jats:italic>\n                      levels in tumor tissue samples were associated with increased infiltration levels of M1 macrophages, CD8\n                      <jats:sup>+<\/jats:sup>\n                      and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>IFI30 exerts a negative modulation on CTSL to regulate IFNGR1, PD-L1, and MHC-II levels during IFN-\u03b3 stimulation. IFI30 levels may represent a key regulatory factor of IFN-\u03b3 pathway associated with ICI responses in MM patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-026-02710-9","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T09:19:05Z","timestamp":1770887945000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Interferon-gamma-inducible protein 30 prevents IFN-\u03b3-receptor 1 degradation to maintain PD-L1 and MHC-II levels in metastatic melanoma"],"prefix":"10.1186","volume":"24","author":[{"given":"Shodai","family":"Mizuno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Mizuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kodai","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Macy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly K.","family":"Chong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen T.","family":"Hastings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave S. 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