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Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Approach and results<\/jats:title>\n                  <jats:p>The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (EN<jats:sup>KO<\/jats:sup>) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from EN<jats:sup>KO<\/jats:sup> mice had increased CD8<jats:sup>+<\/jats:sup> T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8<jats:sup>+<\/jats:sup> T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9\/10 expression and secretion, resulting in the suppression of CD8<jats:sup>+<\/jats:sup> T cell infiltration. High level of endosialin protein expression was correlated with low CD8<jats:sup>+<\/jats:sup> T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Endosialin could inhibit CD8<jats:sup>+<\/jats:sup> T cell infiltration by inhibiting the expression and secretion of CXCL9\/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-009111","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T02:00:52Z","timestamp":1726020052000},"page":"e009111","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Endosialin-positive CAFs promote hepatocellular carcinoma progression by suppressing CD8<sup>+<\/sup> T cell infiltration"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4394-0565","authenticated-orcid":false,"given":"Lunbiao","family":"Gan","sequence":"first","affiliation":[{"name":"Xi\u2019an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 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