{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T02:20:58Z","timestamp":1794277258032,"version":"4.9.0"},"reference-count":31,"publisher":"Baishideng Publishing Group Inc.","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["World J Gastrointest Oncol"],"abstract":"<jats:p>BACKGROUND<\/jats:p>\n          <jats:p>Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) are beneficial to the resumption of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies. However, ICIs with a single target exhibit poor overall response rate in hepatocellular carcinoma (HCC) patients due to the complex pathological mechanisms of HCC.<\/jats:p>\n          <jats:p>AIM<\/jats:p>\n          <jats:p>To investigate the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model, aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.<\/jats:p>\n          <jats:p>METHODS<\/jats:p>\n          <jats:p>The levels of PD-1 and TIM-3 on CD4+ and CD8+ T cells from tumor tissues, ascites, and matched adjacent tissues from HCC patients were determined with flow cytometry. An HCC xenograft mouse model was established and treated with anti-TIM-3 monoclonal antibody (mAb) and\/or anti-PD-1 mAb. Tumor growth in each group was measured. Hematoxylin and eosin staining and immunohistochemical staining were used to evaluate T cell infiltration in tumors. The percentage of CD4+ and CD8+ T cells in tissue samples from mice was tested with flow cytometry. The percentages of PD-1+CD8+, TIM-3+CD8+, and PD-1+TIM-3+ CD8+ T cells was accessed by flow cytometry. The levels of the cytokines including tumor necrosis factor alpha (TNF-\u03b1), interferon-\u03b3 (IFN-\u03b3), interleukin (IL)-6, and IL-10 in tumor tissues were gauged with enzyme-linked immunosorbent assay kits.<\/jats:p>\n          <jats:p>RESULTS<\/jats:p>\n          <jats:p>We confirmed that PD-1 and TIM-3 expression was substantially upregulated in CD4+ and CD8+ T cells isolated from tumor tissues and ascites of HCC patients. TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight, while combined blockade had more substantial anti-tumor effects than individual treatment. Then we showed that combined therapy increased T cell infiltration into tumor tissues, and downregulated PD-1 and TIM-3 expression on CD8+ T cells in tumor tissues. Moreover, combined treatment facilitated the production of T cell effector cytokines TNF-\u03b1 and IFN-\u03b3, and reduced the production of immunosuppressive cytokines IL-10 and IL-6 in tumor tissues. Thus, we implicated that combined blockade could ameliorate T cell exhaustion in HCC mouse model.<\/jats:p>\n          <jats:p>CONCLUSION<\/jats:p>\n          <jats:p>Combined TIM-3 and PD-1 blockade restrains HCC development by facilitating CD4+ and CD8+ T cell-mediated antitumor immune responses.<\/jats:p>","DOI":"10.4251\/wjgo.v15.i12.2138","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T04:58:17Z","timestamp":1702443497000},"page":"2138-2149","source":"Crossref","is-referenced-by-count":18,"title":["Combined TIM-3 and PD-1 blockade restrains hepatocellular carcinoma development by facilitating CD4+ and CD8+ T cell-mediated antitumor immune 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