Loss of DNA Repair Drives Neoantigen Renewal and Inhibits Tumor Growth

Mutations in genes associated with DNA mismatch repair (MMR), such as MLH1, result in a microsatellite instability (MSI) phenotype and promote tumor initiation and growth; however, MMR-deficient cancers are associated with favorable prognosis. It has recently been shown that immune checkpoint blockade is more efficacious in patients with MSI tumors than in patients with microsatellite stable (MSS) tumors. To elucidate the role of MMR in tumorigenesis and immunotherapy response, Germano and colleagues performed CRISPR/Cas9-mediated targeting of Mlh1 in murine breast, colon cancer, and pancreatic ductal adenocarcinoma cells to generate isogenic sets of MMR-proficient and MMR-deficient cell lines. While both MMR-proficient and MMR-deficient cells grew at similar rates and rapidly formed tumors in immunocompromised mice, only MMR-proficient cells formed subcutaneous and orthotopic tumors in immune-competent syngeneic mice; however, transplantation of MMR-deficient tumors grown in immunocompromised mice to immune-competent mice resulted in tumor growth. Treatment with combined anti–PD-1 and anti-CTLA4 antibodies resulted in decreased growth of transplanted MMR-deficient tumors, but not MMR-proficient tumors, in immune-competent mice. Consistent with these findings, MMR-deficient cells formed tumors in immune-competent mice depleted of CD8⁺ T cells. Longitudinal exome sequencing revealed that mutational load, the number of neoantigens, and T-cell receptor diversity increased over time in MMR-deficient, but not MMR-proficient, cells. Further, treatment with the genotoxic agent temozolomide inactivated MMR in MMR-proficient cancer cells, resulting in increases in mutational load and neoantigens and enhanced tumor immune surveillance in vivo. Similarly, decreased expression of the DNA repair enzyme MGMT in human cancer cells and tumors treated with temozolomide was associated with alterations in MMR genes and high tumor mutation burden and number of neoantigens. These findings show that MMR deficiency induces neoantigen production to promote durable immune surveillance and suggest that inactivation of DNA repair may enhance the immunogenicity of MSS tumors.

Germano G, Lamba S, Rospo G, Barault L, Magrì A, Maione F, et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017;552:116–20.

• ©2018 American Association for Cancer Research.