Abstract
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 ε, the leading strand replicase encoded by POLE. 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 LSL-PoleP286R 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 Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. 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 POLE-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.
Highlights
DNA mutations are the fundamental drivers of cancer [1]
These results demonstrate that p53 mutations are common but relatively late events in PoleP286R tumor progression, consistent with human POLE endometrial cancers, and show that p53 mutations occurred more frequently and presumably earlier in PoleP286R/+Msh2–/– tumors, perhaps as an adaptation to increased mutation rate
We present a potentially novel and efficient conditional, tissue-specific approach using an LSL-PoleP286R allele to generate a specific cancer mouse model with a far higher mutational burden than previously feasible in live genetically engineered animal models
Summary
DNA mutations are the fundamental drivers of cancer [1]. a central hallmark of cancer is an incidence of mutations more numerous than can be explained on the basis of the intrinsic mutation rate of normal (nonmalignant) cells [2, 3]. Systematic characterization of cancer genomes has underscored the high incidence of mutations in most cancers — especially carcinomas — and the underlying mutator mechanisms that initiate cancers and support subsequent diversification. These “mutator phenotypes” reflect the complexity of pathways that ensure high DNA replication fidelity and repair DNA damage sustained from mutagens, such as ionizing ultraviolet radiation and environmental toxicants, as well as the mutagenic potential of normal cell-intrinsic metabolic processes [3, 4]. In many if not most cancers, the acquisition of a mutator phenotype is the initial instigating event driving tumorigenesis. Defective mismatch repair (dMMR) is common in endometrial and gastrointestinal carcinomas, and experimental evidence (genetic, genomic, mouse models, etc.) points to dMMR as the initial cancer-driving event [5,6,7]
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