: Colorectal cancer (CRC) remains one of the major causes of cancer death worldwide. Chemotherapy continues to serve as the primary treatment modality, while immunotherapy is largely ineffective for the majority of CRC patients. Seminal discoveries have emphasized that modifying DNA damage response (DDR) mechanisms confers both cell-autonomous and immune-related vulnerabilities across various cancers. In CRC, approximately 15% of tumours exhibit alterations in the mismatch repair (MMR) machinery, resulting in a high number of neoantigens and the activation of the type I interferon response. These factors, in conjunction with immune checkpoint blockades, collectively stimulate anticancer immunity. Furthermore, although less frequently, somatic alterations in the homologous recombination (HR) pathway are observed in CRC; these defects lead to genome instability and telomere alterations, supporting the use of poly (ADP-ribose) polymerase (PARP) inhibitors in HR-deficient CRC patients. Additionally, other DDR inhibitors, such as Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitors, have shown some efficacy both in preclinical models and in the clinical setting, irrespective of MMR proficiency. The aim of this review is to elucidate how preexisting or induced vulnerabilities in DNA repair pathways represent an opportunity to increase tumour sensitivity to immune-based therapies in CRC.

DNA repair-dependent immunogenic liabilities in colorectal cancer: opportunities from errors / V. Amodio, P.P. Vitiello, A. Bardelli, G. Germano. - In: BRITISH JOURNAL OF CANCER. - ISSN 1532-1827. - (2024), pp. 1-15. [10.1038/s41416-024-02848-8]

DNA repair-dependent immunogenic liabilities in colorectal cancer: opportunities from errors

G. Germano
Ultimo
Conceptualization
2024

Abstract

: Colorectal cancer (CRC) remains one of the major causes of cancer death worldwide. Chemotherapy continues to serve as the primary treatment modality, while immunotherapy is largely ineffective for the majority of CRC patients. Seminal discoveries have emphasized that modifying DNA damage response (DDR) mechanisms confers both cell-autonomous and immune-related vulnerabilities across various cancers. In CRC, approximately 15% of tumours exhibit alterations in the mismatch repair (MMR) machinery, resulting in a high number of neoantigens and the activation of the type I interferon response. These factors, in conjunction with immune checkpoint blockades, collectively stimulate anticancer immunity. Furthermore, although less frequently, somatic alterations in the homologous recombination (HR) pathway are observed in CRC; these defects lead to genome instability and telomere alterations, supporting the use of poly (ADP-ribose) polymerase (PARP) inhibitors in HR-deficient CRC patients. Additionally, other DDR inhibitors, such as Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitors, have shown some efficacy both in preclinical models and in the clinical setting, irrespective of MMR proficiency. The aim of this review is to elucidate how preexisting or induced vulnerabilities in DNA repair pathways represent an opportunity to increase tumour sensitivity to immune-based therapies in CRC.
Settore BIOS-13/A - Istologia ed embriologia umana
   PEDIATRIC LUNG &HEART COMPLICATIONS OF HIV INFECTION-268896037
   National Institutes of Health
   DIVISION OF LUNG DISEASES
   N01HR096037-027

   Targeting DNA repair pathways, sparking anti cancer immunity
   TARGET
   European Commission
   Horizon 2020 Framework Programme
   101020342
2024
13-set-2024
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1102629
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