Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth

The inactivation of DNA mismatch repair in cancer cells produces dynamic mutational profiles and generates neoantigens, which result in improved immune surveillance against these cells. Tumours impaired by DNA disrepair Inactivation of DNA repair is a common oncogenic process, which increases mutational load in tumours and promotes growth. The authors show that, consistent with the notion that increased mutational load can enhance the immunogenicity of tumours, inactivation of a form of DNA repair called mismatch repair (MMR) can increase the number of neoantigens in tumours. In mice, an increase in neoantigens from MMR inactivation triggered an increase in immune surveillance. MMR inactivation can happen after some forms of chemotherapy, or can potentially be induced, which opens up the possibility of enhancing the effect of immunotherapy by increasing the genetic instability of tumours. Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression 1 . Cancers deficient in MMR frequently show favourable prognosis and indolent progression 2 . The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo , whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. These results suggest that targeting DNA repair processes can increase the burden of neoantigens in tumour cells; this has the potential to be exploited i