{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:03:46Z","timestamp":1792811026637,"version":"4.5.0"},"reference-count":73,"publisher":"American Society for Clinical Investigation","issue":"14","funder":[{"name":"NCI","award":["R01CA211339"],"award-info":[{"award-number":["R01CA211339"]}]},{"name":"NCI","award":["R01CA237405"],"award-info":[{"award-number":["R01CA237405"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,23]]},"abstract":"<jats:p>\n                    Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase \u03b5, the leading strand replicase encoded by\n                    <jats:italic>POLE<\/jats:italic>\n                    . Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional\n                    <jats:italic>\n                      LSL-Pole\n                      <jats:sup>P286R<\/jats:sup>\n                    <\/jats:italic>\n                    allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of\n                    <jats:italic>Pole<\/jats:italic>\n                    -driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of\n                    <jats:italic>Msh2<\/jats:italic>\n                    . Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following immune checkpoint therapy. This model predicts that human\n                    <jats:italic>POLE<\/jats:italic>\n                    -driven cancers will prove consistently responsive to immune checkpoint blockade. Furthermore, this is a robust and efficient approach to recapitulate in mice the high mutational burdens and immune responses characterizing human cancers.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.138829","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T11:01:30Z","timestamp":1595415690000},"source":"Crossref","is-referenced-by-count":42,"title":["A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0263-1335","authenticated-orcid":true,"given":"Hao-Dong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of 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