T-Cell Synaptosomes Orchestrate Long-Term Anti-Tumor Immunity via Proliferative and Metabolic Reprogramming 2266860

Abstract

Abstract Introduction T-cell activation requires intimate contact with antigen-presenting cells (APCs), during which activated T cells deposit microvesicles termed T-cell immunological synaptosomes (TIS) onto APCs. Although TIS can activate APCs, their broader in vivo roles are largely unknown. We asked whether antigen-independent, systemic delivery of TIS could durably reprogram innate compartments and elicit antitumor immunity. Methods TIS were harvested ex vivo from activated T cells and administered intraperitoneally to mice. Cellular uptake, persistence, and time-course changes in immune cell composition were assessed by flow cytometry. Functional reprogramming was profiled by transcriptomic analysis and by cytokine and chemokine quantification, using LPS as a control. Antitumor efficacy was evaluated in the MC38 colon cancer model and by tumor rechallenge. Results Here, we show that TIS are primarily phagocytosed by macrophages and dendritic cells, persist intracellularly for several days, and reprogram these cells in a manner distinct from LPS. TIS upregulate genes involved in metabolism, proliferation, and anti-inflammatory responses, and promote immune cell recruitment, including eosinophils. Notably, TIS induce minimal immune activation upon initial exposure but trigger a rapid and robust response upon secondary administration, indicating a priming effect reminiscent of adaptive immunity.In an MC38 colon cancer model, TIS treatment resulted in near-complete tumor suppression and durable protection upon rechallenge. Conclusion Systemically delivered TIS act as adhesion derived vesicular effectors that durably reprogram immunity, inducing trained immunity like priming and bridging adaptive and innate arms. These properties position TIS as a potent, long-lasting, vesicle-based platform for cancer immunotherapy. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)