{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T11:30:41Z","timestamp":1773747041883,"version":"3.50.1"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T00:00:00Z","timestamp":1642896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T00:00:00Z","timestamp":1642896000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Immunotherapy with programmed cell death 1 (PD\u20101)\/programmed death ligand 1 (PD\u2010L1) blockade has shown low response rates in liver cancer patients, with the underlying mechanisms unclear. To decipher a specific impact of the liver microenvironment, we compared the effects of anti\u2010PD\u2010L1 antibody (\u03b1PD\u2010L1) blockade on the same tumor grown s.c. or in the liver.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We generated s.c. tumors in mice by inoculating MC38 colorectal cancer (CRC) cells under the skin and metastatic liver tumors by portal vein or splenic injection of CRC cells. Tumor\u2010bearing mice were treated by i.p. injection of \u03b1PD\u2010L1, polyinosinic:polycytidylic acid (poly[I:C]), or both. \u03b1PD\u2010L1 monotherapy significantly suppressed s.c. tumor growth, but showed no effect on metastatic liver tumors. However, the combination of \u03b1PD\u2010L1 with poly(I:C), an innate immunity\u2010stimulating reagent, robustly inhibited tumor progression in liver. The combination therapy effectively down\u2010regulated myeloid\u2010derived suppressor cells (MDSCs), but up\u2010regulated ratios of M1\/M2 macrophages, CD8\/CD4, and CD8\/regulatory T (Treg) cells infiltrated into liver tumors and whole liver. A group of long\u2010lasting T\u2010bet<jats:sup>+<\/jats:sup>Eomes<jats:sup>\u2212<\/jats:sup>PD\u20101<jats:sup>\u2212<\/jats:sup> cytotoxic T cells was maintained in the combo\u2010treated liver, leading to resistance to tumor recurrence. Depleting macrophages or blocking type \u2160 interferon signaling abrogated the synergistic antitumor effect of \u03b1PD\u2010L1 and poly(I:C), indicating a requirement of boosting innate immunity for optimized activation of cytotoxic T cells by PD\u20101\/PD\u2010L1 blockade.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The poor response of liver cancers to \u03b1PD\u2010L1 therapy is largely attributable to a unique hepatic immunotolerant microenvironment, independent of tumor origins or types. The success of a combinatorial immunotherapy relies on coordinated inhibition or activation of various innate and adaptive immune cell activities.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32266","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T11:13:55Z","timestamp":1638530035000},"page":"630-645","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Enhancing the therapeutic efficacy of programmed death ligand 1 antibody for metastasized liver cancer by overcoming hepatic immunotolerance in mice"],"prefix":"10.1097","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8644-2429","authenticated-orcid":false,"given":"Bing","family":"Xin","sequence":"first","affiliation":[{"name":"Department of Pathology,Division of Biological Sciences and Moores Cancer Center,University of California at San Diego,La Jolla,California,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meixiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology,Division of Biological Sciences and Moores Cancer Center,University of California at San Diego,La Jolla,California,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panyisha","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology,Division of Biological Sciences and Moores Cancer Center,University of California at San Diego,La Jolla,California,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pathology,Division of Biological Sciences and Moores Cancer Center,University of California at San Diego,La Jolla,California,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyu","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Pathology,Division of Biological Sciences and Moores Cancer Center,University of California at San Diego,La Jolla,California,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enfu","family":"Hui","sequence":"additional","affiliation":[{"name":"Section of Cell & Developmental Biology,Division of Biological Sciences,University of California at San Diego,La Jolla,California,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gen\u2010Sheng","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pathology,Division of Biological Sciences and Moores Cancer Center,University of California at San Diego,La 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