IMMU-48. SOLUBLE CIRCULATING IMMUNE CHECKPOINT MOLECULES IN MALIGNANT BRAIN TUMORS

Abstract

Abstract Immune checkpoint therapy has been shown to be effective in several types of cancer, and tumor-directed immune activation is also a promising strategy in glioblastoma (GBM) patients. Our goal was to discover alterations in the circulating immunome of GBM patients and other cerebral tumor entities to identify soluble immune biomarkers and novel therapeutic targets. We analyzed 30 markers in plasma of 208 patients and healthy donors, using bead-based multiplex assays and flow cytometry. In a smaller cohort we further applied a high-sensitivity discovery biomarker platform with 368 markers. We included patients with 1) primary GBM (n=68), 2) recurrent GBM (n=25), 3) cerebral metastases (NSCLC, n=61; breast cancer, n=19), 4) meningioma (n=15) as well as 5) healthy donors (HD, n=20). We detected a distinct immune signature in the peripheral blood of patients with GBM, which was defined by an increased prevalence of soluble immune checkpoint markers (sCD27, sPD-L2, sGal-9), whereas soluble chemokines (CX3CL, CXCL12) were underrepresented. This signature was similar in primary and recurrent GBM, but differed markedly from other cerebral tumor entities as well as from HD. Primary GBM, but not their recurrent counterparts, additionally exhibited increased levels of neurotrophic factors (BDNF, b-NGF) and signs of immune activation with significantly increased levels of IL-18. The biomarker discovery platform further identified 76 proteins that were specifically regulated in GBM compared to HD, offering the potential to serve as biomarkers for disease activity. GBM patients with higher levels of BDNF displayed a significantly shorter survival than patients with lower levels (9.33 vs. 21.90 months; p=0.0001). Likewise patients with high concentrations of VEGF survived significantly shorter than those with low concentrations (12.97 vs. 21.90 months, p=0,0166). Taken together, we were able to delineate a specific immune profile of soluble markers in GBM patients compared to other cerebral tumor entities and to healthy individuals.