ID #137 Harnessing trained immunity in macrophages and resident microglia as a potential strategy against pediatric brain tumors
Akshaya Lakshmi Krishnamoorthy, David Schrijver, Yan Su, Julie Lammers, Thijs van den Broek, Thijs Beldman, Bram Priem, Joost Kreijtz, Stefan Nierkens, Eelco Hoving, Jasper Van der Lugt, Mihai Netea, Tiago Ferreira Carvalheiro, Willem Mulder, Dannis van VuurdenAbstract
Children diagnosed with brain tumors face a dismal prognosis, with poor survival. While immunotherapy has shown significant success in various types of cancer, its application in pediatric brain tumors remains limited. This can be attributed to the immunosuppressive tumor microenvironment (TME) and the underappreciated role of the myeloid cells compartment, which often constitutes 70–75% of the immune cell population in these tumors. Moreover, it is well described that innate immunity is highly adaptive and robust in children. Therefore, activating innate immunity, systemically by targeting peripheral myeloid cells or locally by modulating resident microglia, in pediatric brain tumors is an attractive strategy to overcome the immunosuppressive TME.
As a proof-of-concept, we here aim to induce trained immunity in monocytes and microglia derived from pediatric brain tumor patients toward a pro-inflammatory, anti-tumoral phenotype using microbial stimuli, including Heat-killed Candida albicans (HKCA), β-glucan, lipopolysaccharide (LPS), and Bacillus Calmette–Guérin (BCG).
To investigate the systemic induction of trained immunity, we exposed peripheral blood mononuclear cells (PBMCs) derived from pediatric brain tumor patients to different microbial stimuli. Notably, HKCA exposure resulted in robust induction in trained immunity in PBMCs, with enhanced cytokine responses observed six days post-training upon LPS re-stimulation. Cytokine profiling revealed elevated levels of IL-6, TNF-α, IFN-γ, and Granzyme-B with reduced IL-10, indicating an enhanced pro-inflammatory program with concomitant reduction in anti-inflammatory responses.
As a model for local trained immunity induction, we developed in vitro assays using iPSC-derived microglia. Interestingly, HKCA demonstrated a robust training effect in microglia following LPS challenge after three days. Trained microglia exhibited not only increased pro-inflammatory activity (IL-6, TNF-α), but also improved endocytic function and elevated metabolic activity, including increased glycolytic ATP production and lactate levels that are hallmarks of innate immune training.
Taken together, these findings provide evidence that trained immunity can be effectively induced in both peripheral and CNS-resident myeloid cells using HKCA. Given the highly robust and responsive nature of innate immune system in children, by reprogramming myeloid cells toward a sustained, pro-inflammatory phenotype, we aim to increase anti-tumor immunity in the TME of pediatric brain tumor patients.