Abstract
BackgroundIn a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC).Methodology/Principal FindingsMonocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 (“conv. mix”). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC.ConclusionExcellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy.
Highlights
Dendritc cells (DC) are specialized, highly potent antigen presenting cells (APC) that are capable of inducing primary immune responses in vivo [1]
Excellent ability of IRX-2 to induce ex vivo dendritic cells (DC) maturation in head and neck squamous cell carcinoma (HNSCC) patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy
Little attention has been paid to the ability of DC from cancer patients to process and present tumor antigen (TA), a process involving the components of the antigen processing machinery (APM), which is required for the delivery of signal 1 in the induction of primary Tcell responses
Summary
Dendritc cells (DC) are specialized, highly potent antigen presenting cells (APC) that are capable of inducing primary immune responses in vivo [1]. DC showing an immature phenotype (iDC) with reduced abilities to prime T cell responses were present in patients with colorectal and breast cancer [3,4]. In HNSCC patients, accumulations of these iDC correlated with a poor prognosis [5,6] These iDC express low levels of co-stimulatory molecules, and may not be able to provide signal 2 necessary for priming of T-cell responses. In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC)
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