HLA-A*0201 + Plasmacytoid Dendritic Cells Provide a Cell-Based Immunotherapy for Melanoma Patients

Abstract

Several sources of evidence suggest that tumor-specific T cells have the potential to control melanoma tumors. Current active and adoptive therapeutic approaches to elicit such T cells are either not sufficiently clinically efficient or require fastidious processes that impede their extensive clinical use. As plasmacytoid dendritic cells (pDCs) have a crucial role in triggering antitumor immunity especially in melanoma, we explored their potential as a cell-based approach for melanoma immunotherapy. An irradiated human HLA-A(*)0201(+) pDC line loaded with peptides derived from the major melanoma tumor antigens, MelA/MART-1, gp100/pmel17, tyrosinase, and MAGE-A3, was used to trigger functional multi-specific T cells ex vivo from peripheral blood mononuclear cells and tumor-infiltrating lymphocytes from stage I-IV HLA-A(*)0201(+) melanoma patients. pDCs loaded with melanoma-derived peptides promptly induced high levels of melanoma tumor-specific T cells from both sources. pDC-primed central/effector memory antitumor T cells were highly functional as indicated by the specific IFNγ secretion and membrane CD107 expression upon stimulation. Cells also exhibited strong cytotoxicity toward semi-allogeneic melanoma cells and patient-derived tumor cells. The simple design and potent efficacy of this promising approach provides a preclinical basis for the development of a pDC-based vaccine and an alternative means to produce tumor-specific T cells for adoptive cellular immunotherapy in melanoma patients.

Trial watch

“…Along similar lines, the research group lead by Nadege Goutagny (Léon Bérard Research Center, Lyon, France) has demonstrated that the intratumoral administration of TLR7 agonists can restore the ability of pDCs to drive a robust, Type I IFN-dependent tumor-specific immune response 259 . Together with the clinical and preclinical results published by Tel and colleagues, 240 , 260 these results might pave the way toward harnessing the immunostimulatory potential of pDCs for anticancer immunotherapy 261 , 263 , 335 , 336 …”

“…At least apparently, this is at odds with the association between high intratumoral levels of pDCs and poor disease outcome, which holds true in patients affected by several tumor types 32 , 96 , 99 , 100 , 259 . Thus, contrarily to previous beliefs, it may be possible to harness not only cDCs, but also pDCs, for anticancer immunotherapy 260 - 263 …”

pDCs efficiently process synthetic long peptides to induce functional virus‐ and tumour‐specific T‐cell responses

“…Plasmacytoid DCs (pDCs) are another interesting DC subset, also playing a critical role in shaping and regulating immune responses [25,26]. pDCs appear as novel vectors for immunotherapy for both cancer and infections [27][28][29][30], but their ability to cross-present SLP has never been investigated. Nonetheless, there is increasing evidence that pDCs effectively capture, process, and present antigens to T cells [31], including soluble and particulate antigens [32], lipopeptides and cell-associated antigens from apoptotic cells [33], viral particles [34], viral antigens from influenza-exposed cells [35] and tumour antigens (NY-ESO1) from measles virus infected tumour cells [36].…”

The Dark Side of Dendritic Cells: Development and Exploitation of Tolerogenic Activity That Favor Tumor Outgrowth and Immune Escape

“…Two different approaches using PDC have been developed. A leukemic cell line with PDC characteristic has been isolated and, after having demonstrated functional activity in humanized murine models (140) and with melanoma PBL in vitro (141) will be evaluated in a clinical trial in HLA-matched melanoma patients (NCT01863108). In contrast, de Vries and co-workers have employed autologous, patient-derived PDC in a phase I clinical trial against melanoma (142).…”