Significant anti-tumour activity of adoptively transferred T cells elicited by intratumoral dendritic cell vaccine injection through enhancing the ratio of CD8+ T cell/regulatory T cells in tumour

Abstract

SummaryWe have shown that immunization with dendritic cells (DCs) pulsed with hepatitis B virus core antigen virus-like particles (HBc-VLP) packaging with cytosine-guanine dinucleotide (CpG) (HBc-VLP/CpG) alone were able to delay melanoma growth but not able to eradicate the established tumour in mice. We tested whether, by modulating the vaccination approaches and injection times, the anti-tumour activity could be enhanced. We used a B16-HBc melanoma murine model not only to compare the efficacy of DC vaccine immunized via footpads, intravenously or via intratumoral injections in treating melanoma and priming tumour-specific immune responses, but also to observe how DC vaccination could improve the efficacy of adoptively transferred T cells to induce an enhanced anti-tumour immune response. Our results indicate that, although all vaccination approaches were able to protect mice from developing melanoma, only three intratumoral injections of DCs could induce a significant anti-tumour response. Furthermore, the combination of intratumoral DC vaccination and adoptive T cell transfer led to a more robust anti-tumour response than the use of each treatment individually by increasing CD8 + T cells or the ratio of CD8 + T cell/regulatory T cells in the tumour site. Moreover, the combination vaccination induced tumour-specific immune responses that led to tumour regression and protected surviving mice from tumour rechallenge, which is attributed to an increase in CD127-expressing and interferon-g-producing CD8+ T cells. Taken together, these results indicate that repeated intratumoral DC vaccination not only induces expansion of antigen-specific T cells against tumour-associated antigens in tumour sites, but also leads to elimination of pre-established tumours, supporting this combined approach as a potent strategy for DC-based cancer immunotherapy.

Modulation of Regulatory T Cell Function by Monocyte-Derived Dendritic Cells Matured through Electroporation with mRNA Encoding CD40 Ligand, Constitutively Active TLR4, and CD70

“…In cancer, they are critically important for activating CD8 + T cells into potent cytotoxic T cells capable of lysing tumor cells (22,23). DCs are indeed capable of inducing T eff , depending on the stimulus by which these DCs have been activated.…”

A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma

“…Lutz-Nicoladoni et al [27] as well as Koike et al [26] showed delayed tumor outgrowth or better survival and tumor regression as a result of this combination treatment in >40 % of animals inoculated with aggressive tumors. Song et al [29] as well as Tamai et al [30] had similar findings and showed that combination treatment led to T cell infiltration into the primary tumor, as well as into metastases and induced immunological memory that protected the mice from re-challenge.…”

“…Studies from several mouse models have suggested that the combination of DC vaccination with ACT is superior to single agent treatments [26][27][28][29][30]. Lutz-Nicoladoni et al [27] as well as Koike et al [26] showed delayed tumor outgrowth or better survival and tumor regression as a result of this combination treatment in >40 % of animals inoculated with aggressive tumors.…”

Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells

“…administered Type-1 anti-tumor CD8 + T cells in a CXCL10/IP-10 chemokine-dependent manner (60). Also in this light, several recent reports (61–63) are intriguing since i.t. delivery of DC loaded with tumor antigens (versus unloaded DC) was observed to maximally enhance the accumulation and anti-tumor efficacy of adoptively-transferred or vaccine-induced tumor antigen-specific CD8 + T cells.…”