Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth
| Autor: | Giulia Lerda, Federica Morano, Salvatore Siena, Mariangela Russo, Alice Bartolini, Ludovic Barault, Federica Maione, Alessandro Magrì, Filippo Pietrantonio, Giovanni Germano, Enrico Giraudo, Monica Montone, Benedetta Mussolin, Maurizio D'Incalci, Silvia Marsoni, Federica Di Nicolantonio, Giulia Siravegna, Giovanni Crisafulli, Alberto Bardelli, Andrea Sartore-Bianchi, Armando Orlandi, Giuseppe Rospo, Filippo de Braud, Roberta Frapolli, Nabil Amirouchene-Angelozzi, Simona Lamba |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Antibodies Neoplasm DNA repair Receptors Antigen T-Cell cancer genetics Mice SCID MLH1 DNA Mismatch Repair Mice 03 medical and health sciences Antigen Antigens Neoplasm Mice Inbred NOD Cell Line Tumor Neoplasms medicine Animals cancer Multidisciplinary cancer cancer genetics Cell Proliferation Genetics Mice Inbred BALB C Settore MED/06 - ONCOLOGIA MEDICA Multidisciplinary biology Cancer medicine.disease neoantigen digestive system diseases 3. Good health Mice Inbred C57BL Transplantation 030104 developmental biology Cancer cell Cancer research biology.protein Female Tumor Escape DNA mismatch repair Immunotherapy Antibody MutL Protein Homolog 1 |
| Zdroj: | Nature |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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