Comprehensive Analysis of the Functional Landscapes of POLE and POLD1 Mutations in Checkpoint Blockade-Dependent Anti-Tumor Immunity

Defects in DNA damage repair pathways have been linked to improved response to immune checkpoint blockade (ICB), which is primarily attributed to increased tumor mutation burden. Pathogenic mutations in POLE and POLD1 can result in a hypermutator phenotype, but there are significant differences in magnitude and mutational signatures produced depending on individual driver mutations. Hypermutation is thought to be one of the strongest drivers of sensitivity to ICB, yet how the diverse mutations in POLE/POLD1 influence anti-tumor immunity following ICB is unknown. Here, we comprehensively determined the effect of POLE/POLD1 driver mutations on ICB therapy response in patients and isogenic murine models. We generated 5 syngeneic murine models with driver mutations in POLE/POLD1. These mutant tumors accumulated single nucleotide variants and generated mutational signatures that closely resemble human tumors with POLE/POLD1 driver mutations. Furthermore, they displayed enhanced tumor immunity and shifts in immune cell repertoires before and after immunotherapy. Tumors harboring POLE or POLD1 driver mutations were sensitive to ICB therapy compared to their parental models or variants of unknown significance. To evaluate the clinical significance of our findings, we developed a statistical model built on POLE/POLD1 functional mutational signatures that can identify immunologically compliant tumors harboring POLE/POLD1 driver alterations in patients who received immunotherapy. We uncover how POLE/POLD1 mutation-dependent genomic features especially specific mutational signatures shape immunotherapy efficacy and show that patients with POLE/POLD1 mutated tumors harboring telltale driver signatures respond better and survive longer after ICB therapy when compared with POLE/POLD1 wild-type tumors or mutant tumors without signature footprints. Our study has significant utility for the interpretation of POLE and POLD1 mutations in the setting of immune checkpoint blockade treatment. Taken together, our findings reveal the immune landscape of POLE/POLD1 mutations. These observations have substantial implications for our understanding of the genetic basis of immunotherapy benefit.