Elucidating DNA Damage-Dependent Immune System Activation

The DNA-damage response (DDR) network and the immune system are significant mechanisms linked to the normal functioning of living organisms. Extensive observations suggest that agents that damage the DNA can boost immunity in various ways, some of which may be useful for immunotherapeutic applications. Indeed, the immune system can be activated by the DDR network through a number of different mechanisms, such as via (a) an increase in the tumor neoantigen burden, (b) the induction of the stimulator of interferon genes pathway, (c) the triggering of immunogenic cell death, (d) an increase in antigen presentation as a result of the augmented expression of the major histocompatibility complex type I molecule, (e) modification of the cytokine milieu in the tumor microenvironment, and (f) altered expression of the programmed cell death ligand-1. Together, the DDR network may improve the effect of immunostimulatory anticancer agents and provide a basis for devising more efficient treatment strategies, such as combinatorial therapies of DDR targeting drugs and immunomodulators. Here, the molecular mechanisms underlying the immune system's activation by DDR are summarized, along with some of their possible uses in cancer treatment.