Senescence-targeted immunotherapy for cancer prevention and treatment

The induction of senescence is a promising target in anticancer therapy, yet several obstacles limit its exploitation in the clinic.

The overarching goal of this proposal is to uncover the mechanisms that enable transformed and non-transformed senescent cells to subvert T cell dependent anticancer immunity.

The project is organized into two aims:AIM1: To harness immunological vulnerabilities of senescent tumor cells in cancer prophylaxis and therapy: We will exploit the induction of senescence in cancer cells ex vivo as tool to discover cancer neoantigens and develop cancer vaccination interventions amenable to clinical use.

We will also use genetic barcoding technologies to specify the mechanisms that allow tumor senescent cells to escape T cell clearance.AIM2: To identify and target senescence-associated immune checkpoints in the tumor microenvironment.

We will deploy single cell transcriptomics to map immunosuppressive senescent cell populations in the microenvironment of Non-Small Cell Lung Cancer (NSCLC) and identify Senescence Associated Immune Checkpoints (SAICs).

We will test the efficacy of combination strategies based on induction of senescence in tumors and SAICs inhibition in mouse models of NSCLC.Overall, we expect that the results generated in this endeavor will be instrumental to devise novel interventions that combine the immunostimulatory potential of senescence with the inhibition of immunosuppressive features of the process for clinical use.