When cancer cells are damaged or dying, they can release molecules into the tumor microenvironment known as danger-associated molecular patterns (DAMPs). Those molecules may go on to elicit an immune response through a process known as immunogenic cell death whereby cells of the immune system, including cytotoxic T cells, are stimulated to kill more cancer cells. It has been shown that in order to become effective cancer cell killers, T cells need to first be primed by dendritic cells (DCs) and that the presence of activated DCs within the tumor bed is associated with a positive prognostic value. Priming occurs through the help of formyl peptide receptor 1 (FPR1), a G protein-coupled receptor expressed by DCs, that guides them into close proximity of dying cancer cells by sensing DAMPs. Guido Kroemer and his team have previously shown that DCs with mutated FPR1 lose their anticancer potency. In particular, patients with a germline mutation in FPR1 show an accelerated cancer onset- in particular, luminal B breast, colorectal, esophageal, and head and neck cancers.
With this ASPIRE Award, Kroemer and his team will investigate the impact of FPR1 on anticancer immunosurveillance using three approaches: 1) an FPR1 knock-in mouse model that recapitulates the human mutation to study its effect on hormone-induced luminal B breast cancer and inflammation-induced intestinal cancers; 2) a CRISPR/Cas9 system to create a new method of conditionally immortalizing DCs to study the full spectrum of mature DC function and to screen for genes and pharmaceutical candidates that may reverse the immune defect; and 3) a novel technology platform currently under development to study DC migration using ferromagnetic nanoparticles to screen for pharmaceutical agents that may compensate for the mutation. These experiments will shed light on T cell priming, and may reveal new therapeutic targets that can overcome and reverse the cancer-accelerating FPR1 genetic defect.
Carbonnier V, Le Naour J, Bachelot T, Vacchelli E, André F, Delaloge S, Kroemer G. Rs867228 in FPR1 accelerates the manifestation of luminal B breast cancer. Oncoimmunology. 2023.