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.

Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth / G. Germano, S. Lamba, G. Rospo, L. Barault, A. Magrì, F. Maione, M. Russo, G. Crisafulli, A. Bartolini, G. Lerda, G. Siravegna, B. Mussolin, R. Frapolli, M. Montone, F. Morano, F. de Braud, N. Amirouchene-Angelozzi, S. Marsoni, M. D'Incalci, A. Orlandi, E. Giraudo, A. Sartore-Bianchi, S. Siena, F. Pietrantonio, F. Di Nicolantonio, A. Bardelli. - In: NATURE. - ISSN 1476-4687. - 552:7683(2017 Dec 07), pp. 116-120. [10.1038/nature24673]

Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth

F. de Braud;A. Sartore-Bianchi;S. Siena;F. Pietrantonio;
2017

Abstract

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.
Settore MED/06 - Oncologia Medica
7-dic-2017
Article (author)
File in questo prodotto:
File Dimensione Formato  
nature2017f.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 4.07 MB
Formato Adobe PDF
4.07 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/551564
Citazioni
  • ???jsp.display-item.citation.pmc??? 181
  • Scopus 412
  • ???jsp.display-item.citation.isi??? 395
social impact