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Nature. 2017 Dec 7;552(7683):116-120. doi: 10.1038/nature24673. Epub 2017 Nov 29.

Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth.

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Candiolo Cancer Institute - FPO, IRCCS, Candiolo 10060, Turin, Italy.
University of Turin, Department of Oncology, Candiolo 10060, Turin, Italy.
IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan 20156, Italy.
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy.
Department of Oncology and Hemat-Oncology Università degli Studi di Milano, Milan 20122, Italy.
FIRC Institute of Molecular Oncology (IFOM), Milan 20139, Italy.
Policlinico Universitario A. Gemelli, Roma 00168, Italy.
University of Torino, Department of Science and Drug Technology, Turin 10125, Italy.
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan 20142, Italy.


Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression. Cancers deficient in MMR frequently show favourable prognosis and indolent progression. 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.

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