Radiotherapy Induces Innate Immune Responses in Patients Treated for Prostate Cancers

Purpose: Radiotherapy is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced radiotherapy technologies enable treat-ment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell-cycle arrest, cell death, and innate immune response (IIR) stimulation. Experimental Design: To understand systemic clinical res-ponses after radiation exposure, proteomic and metabolomic anal-yses were performed on plasma obtained from patients with cancer at intervals after prostate stereotactic body radiotherapy. Pathway and multivariate analyses were used to delineate molecular altera-tions following radiotherapy and its correlation with clinical outcomes. Results: DNA damage response increased within the first hour after treatment and returned to baseline by 1 month. IIR signaling also increased within 1 hour of treatment but persisted for up to months thereafter. Furthermore, robust IIR and metabolite elevations, consistent with an early proinflammatory M1-mediated innate immune activation, were observed in patients in remission, whereas patients experiencing prostate serum antigen-determined disease progression demonstrated less robust immune responses and M2-mediated metabolite elevations.Conclusions: To our knowledge, these data are the first report of longitudinal proteomic and metabolomic molecular responses in patients after radiotherapy for cancers. The data supports innate immune activation as a critical clinical response of pati-ents receiving radiotherapy for prostate cancer. Furthermore, we propose that the observed IIR may be generalized to the treat-ment of other cancer types, potentially informing multidisciplin-ary therapeutic strategies for cancer treatment.

Automated summary

Radiotherapy is an effective treatment for cancers, which can be used alone or in combination with surgery and chemotherapy. It can cause DNA damage and activate innate immune response, leading to cell cycle arrest, cell death, and immune stimulation.