NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

Abstract

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma. This malignancy is considered virtually incurable, with high response rates to therapy but frequent relapses. We investigated the ability of monocyte-derived dendritic cells generated in the presence of IFN-α and GM-CSF (IFN-DC) and loaded with apoptotic lymphoma cells to activate immune responses against FL cells, with the ultimate goal of designing novel patient-specific vaccination strategies for the treatment of FL. In this article, we show that apoptotic tumor cell–loaded IFN-DC from FL patients, which were cultured for 2 wk with autologous lymphocytes, led to Th1 response skewing, based on significantly higher levels of IFN-γ production and a remarkable increase in CD8+ and NK cell frequency, consistent with the detection of enhanced cytotoxic effector function toward autologous FL cells. IFN-DC were found to promote efficient NK cell activation, increased expression of cytotoxicity receptors, and extensive IFN-γ production in the virtual absence of IL-10. Moreover, direct recognition and killing of primary autologous lymphoma cells by activated NK cells from FL patients was also demonstrated. A critical role was demonstrated for MHC class I–related chain A and B and membrane-bound IL-15 in IFN-DC–mediated NK cell activation and early IFN-γ production. The overall results indicate that IFN-DC loaded with autologous apoptotic FL cells represent a valuable tool for improving the potency of therapeutic cancer vaccines through the efficient induction of NK cell activation and promotion of CD8+ T cell antitumor immunity.

Clearance of HBeAg and HBsAg of HBV in mice model by a recombinant HBV vaccine combined with GM-CSF and IFN-α as an effective therapeutic vaccine adjuvant

“…Monocytes are cells with high differentiation potential and can differentiate into M1 macrophages in the presence of GM-CSF and IFN-γ, or into DC on exposure to GM-CSF and IL-4 [ 53 ]. Since Ronald et al first reported that monocytes could differentiate into DC that had potent ability to elicit T cell immunity on exposure to GM-CSF and IFN-α [ 54 ], multiple reports have recognized the benefit of IFN-α-MoDC vaccines [ 55 , 56 ]. IFN-α is crucial for the generation of Ly6 hi monocytes [ 57 ] and can accelerate DC maturation, promote co-stimulation factor expression and pro-inflammatory cytokine secretion [ 29 ].…”

Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy

“…22 Notably, Lapenta C. et al have recently demonstrated the practicability of the approach based on IFN-DC loaded with autologous apoptotic follicular lymphoma cells. 23 Our findings demonstrated the ability of the highly immunogenic RA/IFNa-TCLs to activate IFN-DCs and make them more efficient in eliciting tumor and antigen-specific CTLs in vitro and in mediating tumor growth inhibition in vivo, compared with IFN-DCs loaded with lysates from untreated or g-irradiated/necrotic cells. In particular, the analysis of T-cell subpopulations stimulated ex vivo by priming with RA/IFNa-TCLs pulsed-DCs suggested a likely contribution of Th1 and Th17 cells in mediating anti-tumor immune responses.…”

“…17,18 In fact, neoplastic cells undergoing ICD showed superior immunogenicity being able to promote strong antitumor responses largely biased toward Th1 immunity. 19,20 On these grounds, we have developed a new DC-based vaccination protocol for aggressive and/or refractory lymphomas which combines the unique features of interferon-conditioned DC (IFN-DC), [21][22][23][24] with highly immunogenic tumor cell lysates (TCL) obtained from lymphoma cells undergoing ICD induced by 9-cis-retinoic acid and IFNa (RA/ IFNa), a drug combination that we herein show to induce a strongly immunogenic apoptosis. Different options of defined cell culture conditions are available for generating relatively large numbers of DCs from cell precursors.…”

Comparison of morphology, phenotypes and function between cultured human IL-4-DC and IFN-DC

“…TNF-α, LPS, CD40L and polyinosinic:polycytidylic acid (poly I:C) was reported to be used to promote the mature of DCs in vitro ( 16 , 17 ). However, disable DCs could be induced by the stimulation of LPS or poly I:C ( 17 ).…”