{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:05:50Z","timestamp":1790636750603,"version":"4.1.0"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":85,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and aims<\/jats:title>\n                    <jats:p>The conserved human correlate of interleukin-18 receptor 1 (IL-18R1)-associated immune states in hepatocellular carcinoma (HCC) remains undefined. We aimed to identify a minimal, reproducible, immune-state component associated with IL18R1 across independent human HCC cohorts and evaluate its clinical relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Publicly available single-cell RNA sequencing datasets from five independent HCC cohorts were analyzed using a unified framework. Paired tumor-adjacent cohorts were prioritized for primary analyses, whereas tumor-only cohorts served as supportive datasets. CD8 T cells were stratified by IL18R1 expression, and tumor-specific enrichment was quantified using difference-in-differences. We validated the spatial transcriptomics using a murine liver tumor Xenium dataset. Clinical relevance was evaluated using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) bulk RNA-seq data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>IL18R1-positive CD8 T cells exhibited a tumor-specific, C\u2013C motif chemokine ligand 5 (CCL5)-centered cytotoxic transcriptional program, consistently enriched across datasets. Alternative IL18R1 stratification confirmed the identified immune program\u2019s robustness. Spatial transcriptomics localized this cytotoxic state in tumor-associated CD8 T cells and highlighted increased expression of Ccl5 and Cxcr3. Tumor-only cohorts demonstrated substantial heterogeneity, highlighting the importance of paired cohort design. In TCGA-LIHC, a composite CCL5-centered cytotoxic core score, not CCL5 alone, was associated with improved overall survival, although this attenuated after adjusting for clinical covariates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The dominant human correlate of an IL18R1-associated immune state in HCC is a compact, CCL5-centered CD8 cytotoxic module, not a broad inflammatory response. This spatially validated unit provides a reproducible framework for HCC immune-state characterization and stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00262-026-04487-9","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T06:14:29Z","timestamp":1783318469000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conserved minimal CD8 cytotoxic immune-state unit in an IL18R1-associated immune program in hepatocellular carcinoma"],"prefix":"10.1007","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3842-1703","authenticated-orcid":false,"given":"Masamichi","family":"Kimura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Nishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Imamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiminori","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"4487_CR1","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1126\/science.1129139","volume":"313","author":"J Galon","year":"2006","unstructured":"Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. 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Therefore, this secondary analysis was exempt from additional institutional review board approval and informed consent requirements. The Xenium spatial transcriptomic analysis was performed using previously generated experimental data in accordance with the relevant institutional framework for animal experimentation.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable because this study used only previously published, publicly available, and de-identified datasets.","order":3,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable because this study did not include identifiable individual participant data or images.","order":4,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"238"}}