Cancerous cells can undergo Therapy-Induced Senescence (TIS) when challenged with low doses of genotoxic drugs such as doxorubicin (DOX). Senescence is characterized by cell cycle arrest, increased immunogenicity and production of inflammatory cytokines, growth factors and metalloproteinases, collectively referred to as Senescence-Associated Secretory Phenotype (SASP). In multiple myeloma (MM), a plasma cell malignancy that develops within the bone marrow, TIS is able to increase NK cells recognition and killing of tumor cells. Emerging evidence indicate that senescent cells accumulate cytosolic DNA, which in turn activates the cGAS-STING pathway, leading to production of IFN-I and other immune-stimulating cytokines. cGAS activation by cytosolic DNA triggers the production of 2'3'-cGAMP, a soluble small molecule that seems to be exported by tumor cells, activating STING in recipient cells. cGAMP and other STING agonists show impressive antitumoral activity in several in vivo models for their capacity to broadly stimulate the immune system. Our preliminary data suggest that DOX-treated senescent MM cells increase the production of cGAMP compared to untreated cells. Moreover, we demonstrated that DOX-conditioned medium can increase NK cells degranulation and induce senescence on bystander MM cells. However, whether cGAMP is responsible for these phenomena is still to be demonstrated. Interestingly, we have some evidence that low doses of cGAMP can induce senescence in MM cells, whereas higher doses seem to trigger apoptosis.
The objective of our proposal is therefore to correlate these phenomena and to investigate the effectiveness of cGAMP released by senescent cells in activating NK cells. This would be the first evidence of cGAMP being an immune-activating SASP component. Furthermore, we aim at enhancing the activity of cGAMP by modulating the function of known or suspected ectoenzymes responsible for cGAMP degradation in the extracellular environment.
