Characterization of the infiltrating immune response to brain metastases after radio- and immunotherapy
Clinical Neurology; Neurosurgery and Neuroradiology
Final Report Abstract
Cerebral metastases are the most common brain tumors in adults and induce significant mortality and morbidity. Systemic and local treatment options are limited. Radiotherapy (RT) and surgery are the main pillars of treatment; however, recurrences are common and survival of patients is limited. Immune checkpoint blockade (ICB) has revolutionized cancer therapy in recent years, however tumors that metastasize to or originate from the brain have proven difficult to treat for several reasons; difficulty in total surgical removal, limited effectiveness of chemo- and radiotherapy and toxicity of treatments. Additionally, because of the immuneprivileged status of the brain, intracerebral tumors are often immunologically “cold” (i.e. non- T cell inflamed), which hampers the efficacy of ICB. We therefore aimed to deepen our understanding of the function of infiltrating myeloid cells in intracerebral tumors after radio- and immunotherapy. Agonists of Stimulator of Interferon Genes (STING) have been explored in multiple tumor models and combined efficacy with immune checkpoint blockade has been suggested to achieve lasting therapeutic effects by reprogramming the myeloid compartment and thus potentiate the antitumor immune response in peripheral tumors. The cyclic GMP-AMP (cGAMP) – STING pathway forms a vital part of the innate immune response to cytosolic double stranded DNA (dsDNA), which is commonly found in cancer cells and is increased through RT. Nanoscale coordination polymers (NCP) capable of delivering the hydrophilic cdi-AMP (CDA) STING agonist (ZnCDA) have been developed at the University of Chicago, however they have not yet been evaluated in their effectiveness against intracerebral tumors and a combinatory approach with ICB has yet to be explored. We were able to show that ZnCDA is able to pass the blood brain barrier in both healthy and tumor-bearing murine brains and selectively accumulate in intracranial tumors, which significantly improved the survival of mice with cerebral tumors. In a separate approach, we identified the EGFR-ligand amphiregulin, which significantly correlated with tumor progression in lung and brain metastasis models after radiotherapy.
Publications
-
Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration. Nature Nanotechnology, 17(12), 1322-1331.
Yang, Kaiting; Han, Wenbo; Jiang, Xiaomin; Piffko, Andras; Bugno, Jason; Han, Chuanhui; Li, Sirui; Liang, Hua; Xu, Ziwan; Zheng, Wenxin; Wang, Liangliang; Wang, Jiaai; Huang, Xiaona; Ting, Jenny P. Y.; Fu, Yang-Xin; Lin, Wenbin & Weichselbaum, Ralph R.
