LAUSR

Dear Editor, As cancer treatments experience technological advancements, radiation therapy (RT) provides a foundational and essential modality for the treatment of various malignancies. Ionizing radiation (IR), a form of RT, is tailored to individual patients during their cancer care and delivered directly at cancer to kill tumor cells while attempting to spare normal tissue. Notably, as the doses of radiation increase, IR has been shown to be damaging to skin and nearby organs. A commonsideeffect of IR is radiationdermatitis, characterizedbyerythema, edema, and desquamation.1 IR also has immune modulatory effects ranging from immunostimulatory to immunosuppressive.2,3 The exact mechanism(s) by which RT to the skin results in local and systemic effects remains unclear, making prevention, diagnosis, and treatment difficult. Studies, including ours, have shown that exposure to environmental carcinogens, pollutants, cigarette smoke, UV radiation, and IR generates reactive oxygen species (ROS). Notably, such ROS-generating pro-oxidative stressors within the cell microenvironment produce a class of potent phospholipid mediators, platelet-activating factor (PAF), and PAF-like agonists (reviewed in Ref. [4]). PAF receptor (PAFR) is a G protein–coupled receptor that has been shown to be involved in mediating both local and systemic immunemodulatory responses of PAF agonists.4 Previous studies by our group have also demonstrated that IR can generate high levels of PAF and oxidized glycerophosphocholineswith PAFR agonistic activity inmultiple tumor cell lines aswell as in human subjects undergoing RT.5 One of the hallmarks of the pro-oxidative stress response is the release of subcellular microvesicle particles (MVP) from various cell types. These MVPs play a role in intercellular communication and the regulation of immune responses associated with PAF through the release of various bioactive components, including cytokines and other lipids that play a vital role in cell-to-cell communications.6 Moreover, studies have highlighted the involvement of acid sphingomyelinase (aSMase) in theproductionofMVP in response tomultiple agents.7,8 Of importance, IR has been demonstrated to result in aSMase activation.9 Given that IR has been shown to induce PAF agonists,5 which are known to trigger MVP release in keratinocytes8,10,11 as well as the