Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity

Abstract

Extracorporeal photochemotherapy (ECP) is a cancer immunotherapy for cutaneous T-cell lymphoma (CTCL) operative in more than 350 centers worldwide. Although its efficacy and favorable safety profile have driven its widespread use, elucidation of its underlying mechanism has been difficult. In this study, we identify the principal contributors to the anticancer immunotherapeutic effects of ECP, with the goal of enhancing potency and broadening applicability to additional malignancies. First, we scaled down the clinical ECP leukocyte-processing device to mouse size. Second, we used that miniaturized device to produce a cellular vaccine that regularly initiated therapeutic antimelanoma immunity. Third, we individually subtracted key factors from either the immunizing inoculum or the treated animal to ascertain their contribution to the antimelanoma response. Platelet-signaled monocyte-to-dendritic cell (DC) differentiation followed by sorting/processing/presentation of tumor antigens derived from internalized apoptotic tumor cells were absolute requirements. As in clinical ECP, immunogenic cell death of tumor cells was finely titrated by DNA cross-linkage mediated by photoactivated 8-methoxypsoralen (8-MOPA). ECP-induced tumor-loaded DC were effective immunotherapeutic agents only if they were spared exposure to 8-MOPA, indicating that healthy DC are required for ECP. Infusion of responder T cells into naïve tumor-challenged mice established the protective role of stimulated T-cell antitumor immunity. Collectively, these results reveal that selective antitumor effects of ECP are initiated by tumor antigen-loaded, ECP-induced DC, which promote potent collaboration between CD4 and CD8 tumor-specific T cells. These mechanistic insights suggest potential therapeutic applicability of ECP to solid tumors in addition to CTCL. These findings identify principal cellular contributors to the anticancer immunotherapeutic impact of ECP and suggest this treatment may be applicable to a broad spectrum of immunogenic malignancies. .

Platelet P-selectin initiates cross-presentation and dendritic cell differentiation in blood monocytes

“…Platelets showcased a capacity to rapidly differentiate circulating blood monocytes into APCs capable of robust adaptive immune stimulation, specifically through activation of cross-presentation programming. Platelet association resulted in another phenomenon prototypic of DC maturation (14,16), as CD11b + CD11c + monocytes were also observed to up-regulate MHC II expression ( Fig. 2F), further supporting that platelets may supplant inflammatory signals or maturation cocktails in generating DC-like APCs.…”

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

“…Open access the ubiquitin-specific peptidase inhibitor spautin-1, the antibiotic bleomycin, the protein phosphatase-2A inhibitor LB-100, the Chinese herbal medicine component shikonin and capsaicin [34][35][36][37][38] and (8) numerous physical interventions, encompassing various forms of ionizing radiation, extracorporeal photochemotherapy, hypericinbased photodynamic therapy (PDT), near-infrared photoimmunotherapy, high hydrostatic pressure, severe cytotoxic heat shock, nanopulse stimulation and electrohyperthermia. [39][40][41][42][43][44][45][46][47][48][49] Importantly, dose and administration schedules have a major impact on the ability of many of these agents to initiate productive ICD. [50][51][52] The aforementioned ICD inducers have been instrumental not only for identifying the molecular machinery that underlies the immunogenicity of some variants of RCD, 5 but also for elucidating the pathophysiological and therapeutic implications of the process.…”

Sensitive Photodynamic Detection of Adult T-cell Leukemia/Lymphoma and Specific Leukemic Cell Death Induced by Photodynamic Therapy: Current Status in Hematopoietic Malignancies

“…Such a finding suggests that ECP may induce an immune-mediated response to malignant cells, as well as direct killing. The possible mechanism is proposed as follows: the induction of apoptosis of malignant T cells, maturation of dendritic cells (DCs), presentation of tumor-loaded DCs to CTL, and expansion of a population of CTLs against the malignant cells [89,[92][93][94]. Similar biological effects have also been reported in ALA-PDT [95][96][97].…”