student Gwangju Institute of Science and Technology, United States
Introduction/Rationale: 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.
