Title: High-throughput Genomics for Understanding and Engineering Immune Cell Memory

Abstract: 

Durable and safe immunotherapy begins with a comprehensive view of the immune system. A central feature of that system is immunological memory, the capacity to mount stronger and faster responses after an initial encounter. Because memory plays a critical role in eliminating tumors and recurring infections, understanding how it forms and persists is essential to designing next-generation therapies. Both branches of the immune system contribute to memory: the innate immune system can be “trained,” while the adaptive immune system relies on antigen-specific T and B cells. Recent advances in high-throughput 1D and 3D genomics, combined with CRISPR-based editing, now enable us to dissect and reprogram these systems with unprecedented precision.

My thesis investigates immune memory on two fronts. First, using primary macrophages, I explored how IL-4 priming reshapes 3D chromatin architecture to enhance secondary responses. Micro-Capture-C revealed that IL-4 induces new enhancer–promoter loops, positioning response elements for Toll-like receptors, interferon-gamma, and glucocorticoids near their target promoters. Editing these loop anchors enables targeted reprogramming of innate memory responses.

Second, in adaptive immunity, I demonstrate that the transcription factor FOXO1 programs memory in human CAR-T cells. FOXO1 overexpression promotes a memory-like transcriptional and metabolic state, supports persistence under chronic antigen stress, and improves tumor control. Conversely, loss of FOXO1 accelerates T cell exhaustion and diminishes efficacy. Analysis of patient-derived CAR-T and tumor-infiltrating lymphocyte products shows that FOXO1 expression correlates with clinical response.

Together, these studies reveal how immune memory is encoded through three-dimensional chromatin architecture in macrophages and pioneer-factor-driven remodeling in T cells, and can provide insights for engineering next-generation cell therapies with improved durability and efficacy.

Zoom Link: Please contact Leyre Caracuel for the zoom link.