A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response

• DOI: 10.1172/jci.insight.138829
• Publication Date: 2020-07-22T15:01:30Z
• Authors: Hao-Dong Li; Changzheng Lu; He Zhang; Qing Hu; Junqiu Zhang; Ileana C. Cuevas; Subhransu S. Sahoo; Mitzi Aguilar; Elizabeth G. Maurais; Shanrong Zhang; Xiaojing Wang; Esra A. Akbay; Guo-Min Li; Bo Li; Prasad Koduru; Peter Ly; Yang-Xin Fu; Diego H. Castrillon
• Keywords: Microsatellite Instability; MSH2; Immune checkpoint; Chromosome instability

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 DNA polymerase ε, leading strand replicase encoded POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed recapitulate burdens characterizing human permit study mechanisms underlying clinical responses. Here, we show that activation conditional LSL-PoleP286R allele endometrium sufficient elicit all animals endometrial closely resembling their counterparts, very burden. Diverse investigations uncovered potentially novel aspects Pole-driven tumorigenesis, secondary p53 mutations associated tetraploidy, cooperation defective through inactivation Msh2. Most significantly, there were robust antitumor immune responses increased T cell infiltrates, accelerated tumor growth following depletion, unfailing regression checkpoint therapy. This predicts POLE-driven will prove consistently responsive blockade. Furthermore, this efficient approach mice cancers.