‘Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth’ by authors Giovanni Germano, Simona Lamba, Giuseppe Rospo, Ludovic Barault, Alessandro Magrì, Federica Maione, Mariangela Russo, Giovanni Crisafulli, Alice Bartolini, Giulia Lerda, Giulia Siravegna, Benedetta Mussolin, Roberta Frapolli, Monica Montone, Federica Morano, Filippo de Braud, Nabil Amirouchene-Angelozzi, Silvia Marsoni, Maurizio D’Incalci, Armando Orlandi, Enrico Giraudo, Andrea Sartore-Bianchi, Salvatore Siena, Filippo Pietrantonio, Federica Di Nicolantonio & Alberto Bardelli was published in Nature and online 29 November 2017.
Abstract: Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression1. Cancers deficient in MMR frequently show favourable prognosis and indolent progression2. 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 in therapeutic approaches.
Read about the role of the Universita degli Studi di Tornino in MErCuRIC here.
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Published 29 November 2017