Extracorporeal Photopheresis: Secreted Factors That Promote Immunomodulation.

Background: Extracorporeal photopheresis (ECP) is a therapy indicated for various T cell-mediated conditions, including cutaneous T-cell lymphoma (CTCL), graft-versus-host disease (GVHD), and solid organ transplant rejection. ECP comprises the treatment of patients' leukocytes with 8-methoxypsoralen and ultraviolet-A light followed by autologous reinfusion. ECP exerts therapeutic immune-stimulatory effects in CTCL and immune regulatory effects in GVHD and solid organ transplant rejection. Besides cellular mediators, secreted molecules can contribute to ECP's therapeutic effect. Methods: We conducted a comprehensive review of the literature on ECP-induced secreted factors and their immunomodulatory roles. Results: 8-Methoxypsoralen/ultraviolet-A treatment drives leukocyte apoptosis, resulting in the release of damage-associated molecular patterns that promote apoptotic cell phagocytosis by dendritic cells (DCs) and promote or impair DC maturation. In CTCL, the increased production of proinflammatory cytokines in photopheresates, including interferon-γ, interleukin (IL)-2, tumor necrosis factor-α, IL-1β, and IL-8, is linked to antitumor responses. Conversely, ECP upregulates anti-inflammatory cytokine production in photopheresates from GVHD patients' cells. Upon reinfusion of photopheresates containing anti-inflammatory factors, untreated immature DCs are converted to tolerogenic DCs with increased IL-10 and transforming growth factor-β secretion and regulatory T cell-inducing functions. In allograft models, ECP increases IL-4, IL-10, and IL-13, which reduce allograft rejection. Moreover, ECP influences the level of immunomodulatory metabolites and the composition of exosomes. However, further research, for example, using multi-omics approaches, are needed to provide a more comprehensive picture of the ECP-induced secretome and to identify relevant factors that could contribute to ECP's therapeutic effects. Conclusions: ECP induces the release of different pro/anti-inflammatory factors in different preexisting conditions that determine different DC maturation status and immunomodulatory effects.