TARGET project aims at testing for the first time the hypothesis that therapeutic inactivation of DNA repair pathways in cancer cells can be exploited for patient benefit by reawakening an anti-tumor immune response against cancer cells.

Genomic instability and molecular heterogeneity, which occur in cancer cells with DNA repair deficiencies, fuel tumor progression and are associated with poor outcome.

However, the small subset of tumors known as microsatellite unstable (MSI) show better prognosis and favorable clinical outcomes when compared to microsatellite stable (MSS) tumors of the same histology. Such instability is due to alterations in DNA mismatch repair (MMR) system that cause high level of molecular heterogeneity, genetic instability, and increased tumor mutational burdens. Importantly, MMR deficient (MMRd) tumors display remarkable response to therapies based on immune checkpoint inhibitors.

This led to the unprecedented ‘pan cancer’ approval of immune therapeutic regimens based on tests to detect MMR deficiency and, in June 2020, to the approval of immune therapy for any solid tumor with high tumor mutational burden.

The favorable prognosis and the response of MSI cancer to immunotherapy seems to be associated with an accumulation of mutations, which unleash adaptive immunity and trigger immunosurveillance.

However, several aspects of this concept remain to be elucidated:

• What are the bases of the extraordinarily long-lasting responses of patients with MMRd tumors?
• Are there other DNA repair defects able to increase immune surveillance and response to immunotherapy?
• Can we pharmacologically inhibit DNA repair proteins to promote the production of tumor neoantigens allowing the immune system to detect cancer cells?

This unconventional, but possibly high gain approach, builds on the concept that the immune system can identify and selectively target tumor cells carrying DNA alterations and represent the final aim of this project.

By using a multidisciplinary approach and the exploitation of both patient-derived organoids and animal models, we aim at systematically:

• assess whether and how inactivation of DNA repair pathways triggers anticancer immunity and restrict cancer;

• identify DNA repair pathways which, when disabled, reawaken the immune system;

• discover and develop inhibitors of DNA repair proteins able to induce significant increase of immunogenic neoantigens and tumor immunity;

• establish how DNA repair inhibitors and immune modulators can be combined in cancer treatments.