Changes in Blood Biomarkers of Angiogenesis and Immune Modulation after Radiation Therapy and Their Association with Outcomes in Thoracic Malignancies

SIMPLE SUMMARY: Radiation therapy can promote chemotaxis of cytotoxic T-lymphocytes by triggering the release of chemokines and altering the tumor’s vascular endothelium, triggering both pro- and anti-inflammatory immune responses and altering the tumor microenvironment. These effects of local irradiation may have systemic consequences and can be enhanced through the combination of available immune checkpoint blockers (ICBs). The study and validation of minimally invasive blood biomarkers for response and toxicity assessment are critical to stratify patients that would benefit from combination treatments. This exploratory prospective study evaluated the impact of thoracic radiotherapy approaches on the immune system using longitudinal assessment of a panel of blood biomarkers of angiogenesis and inflammation. We show that changes in circulating TNF-α, IL-6 and IL-8 levels could potentially indicate an early reduction in immunosuppression after radiotherapy. If validated in larger studies, these biomarker candidates might potentially help in optimally scheduling radiotherapy in combination with ICBs. ABSTRACT: The effects of radiotherapy on systemic immunity remain to be fully characterized in a disease-specific manner. The aim of the study was to examine potential biomarkers of systemic immunomodulation when using radiotherapy for thoracic malignancies. Serial blood samples were collected from 56 patients with thoracic malignancies prior (RTbaseline), during (RTduring) and at the end of radiotherapy (RTend), as well as at the first (FU1) and second follow-up (FU2). The changes in serum levels of IL-10, IFN-γ, IL-12p70, IL-13, IL-1β, IL-4, IL-6, IL-8, TNF-α, bFGF, sFlt-1, PlGF, VEGF, VEGF-C, VEGF-D and HGF were measured by multiplexed array and tested for associations with clinical outcomes. We observed an increase in the levels of IL-10, IFN-γ, PlGF and VEGF-D and a decrease in those of IL-8, VEGF, VEGF-C and sFlt-1 during and at the end of radiotherapy. Furthermore, baseline concentration of TNF-α significantly correlated with OS. IL-6 level at RTend and FU1,2 correlated with OS (RTend: p = 0.039, HR: 1.041, 95% CI: 1.002–1.082, FU1: p = 0.001, HR: 1.139, 95% CI: 1.056–1.228, FU2: p = 0.017, HR: 1.101 95% CI: 1.018–1.192), while IL-8 level correlated with OS at RTduring and RTend (RTduring: p = 0.017, HR: 1.014, 95% CI: 1.002–1.026, RTend: p = 0.004, HR: 1.007, 95% CI: 1.061–1.686). In conclusion, serum levels of TNF-α, IL-6 and IL-8 are potential biomarkers of response to radiotherapy. Given the recent implementation of immunotherapy in lung and esophageal cancer, these putative blood biomarkers should be further validated and evaluated in the combination or sequential therapy setting.