Immune Checkpoint Blockade Delays Cancer and Extends Survival in DNA Polymerase Mutator Syndromes

Germline Polymerases delta and epsilon (Pold1 and Pole) exonuclease domain mutations are associated with increased cancer incidence. Arising tumors are associated with high tumor mutation burden, increased immune infiltration, enhanced expression of immune checkpoint receptors PDL1 and PD1, and favorable response to immunotherapy with antibodies targeting these receptors (immune checkpoint blockade (ICB)). The elevated tumor mutation burden (TMB) is thought to increase neoantigens and selection for immune evasion through immune checkpoint activation, which may cause increased favorable response to ICB. Whether this is the case or why some tumors with a low TMB respond to ICB and others with a high TMB do not, remains unclear. To address this, we generated mice with germline and conditional mutations in the exonuclease domains of the replicative nuclear DNA polymerases Pold1 and Pole. Engineered mice with these mutator alleles presented with spontaneous cancers, primarily lymphomas, lung, and intestinal tumors, while Pold1 mutant mice also presented with tail skin carcinomas. These cancers have a highly variable tissue-type dependent increased TMB with mutational signatures associated with Pold1 and Pole mutations found in human cancers. The Pold1 mutant tail tumors displayed increased TMB, however, only a subset of these responded to ICB when treated once tumors were established. Introducing these mutator alleles into the low TMB and ICB unresponsive Kras and p53 mouse lung cancer model only moderately increased the TMB and did not affect tumor growth and survival, which was rectified by increasing TMB through passaging in vitro in the absence of immune editing. In contrast to control antibody treatment, treatment of Pold1 and Pole mutant mice with ICB before development of observable tumors increased lifespan and selected for development of tumors without aneuploidy. Thus, elevated TMB can convey response to ICB, possibly through selective elimination of aneuploid clones, which is mitigated by the probability of evolution of resistance mechanisms. These findings raise the possibility of deploying ICB in individuals at risk for high mutation burden cancers for cancer prevention.