We recently reported that bone marrow-derived dendritic cells (DC) from aged miced are less effective than their young counterparts in inducing the regression of B16-ovalbumin (OVA) melanomas. To examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide((257-264)), DCs from aged mice are less efficient than those from young mice in stimulating OVA-specific T cells in vitro. Phenotypic analysis revealed a selective decrease in DC-specific/intracellular adhesion molecule type-3-grabbing nonintegrin (DC-SIGN) level in aged DCs. Adoptive transfer experiments showed defective in vivo DC trafficking in aging. This correlates with impaired in vitro migration and defective CCR7 signaling in response to CCL21 in aged DCs. Interestingly, vaccination of young mice using old OVA peptide((257-264))-pulsed DCs (OVA PP-DC) resulted in impaired activation of OVA-specific CD8(+) T cells in vivo. Effector functions of these T cells, as determined by IFN-gamma production and cytotoxic activity, were similar to those obtained from mice vaccinated with young OVA PP-DCs. A decreased influx of intratumor CD8(+) T cells was also observed. Importantly, although defective in vivo migration could be restored by increasing the number of old DCs injected, the aging defect in DC tumor surveillance and OVA-specific CD8(+) T-cell induction remained. Taken together, our findings suggest that defective T-cell stimulation contributes to the observed impaired DC tumor immunotherapeutic response in aging.

https://cancerres.aacrjournals.org/content/canres/68/15/6341.full.pdf

Impaired dendritic cell function in aging leads to defective antitumor immunity.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with increasing incidence in the western world, about half of them in China. Current curative treatment options for HCC include surgical resection and liver transplantation, but these approaches are restricted to carefully selected patients who may benefit from such interventions. Systemic chemotherapy and transcatheter arterial chemoembolization (TACE) prolong survival of patients who are not eligible for surgical treatment, but these methods only suit for patients with adequate liver function. Therefore, novel alternative treatments such as immunotherapy are currently being evaluated in patients with advanced HCC. Advances in the understanding of tumor immunology have opened new ways to treat certain malignant tumors and may also be the case for patients with HCC in the near future. In this chapter, we will review recent progress in immunotherapy of HCC in the world, including China.

Immunotherapy of Hepatocellular Carcinoma

Dendritic cells (DCs) are the most potent professional antigen-presenting cells, and capable of stimulating naive T cells and driving primary immune responses. DCs are poised to capture antigen, migrate to draining lymphoid organs, and after a process of maturation, select antigen-specific lymphocytes to which they present the processed antigen, thereby inducing immune responses. The development of protocols for the ex vivo generation of DCs may provide a rationale for designing and developing DC-based vaccination for the treatment of tumors. There are now several strategies being applied to upload antigens to DCs and manipulate DC vaccines. DC vaccines are able to induce therapeutic and protective antitumor immunity. Numerous studies indicated that hepatocellular carcinoma (HCC) immunotherapies utilizing DC-presenting tumor-associated antigens could stimulate an antitumour T cell response leading to clinical benefit without any significant toxicity. DC-based tumor vaccines have become a novel immunoadjuvant therapy for HCC.

/pdf/dendritic-cell-as-therapeutic-vaccines-against-tumors-and-3ksiq3badc.pdf

Dendritic cell as therapeutic vaccines against tumors and its role in therapy for hepatocellular carcinoma.

Effective cancer immunotherapy depends on the body’s ability to generate tumor antigen-presenting cells and tumor-reactive effector lymphocytes. As the most potent antigen presenting cells (APCs), dendritic cells (DCs) are capable of sensitizing T cells to new and recall antigens. Clinical trials of antigen-pulsed autologous DCs have been conducted in patients with a number of hematological and solid cancers, including malignant melanoma, lymphoma, myeloma, and non-small cell lung cancer. These studies suggest that antigen-loaded DC vaccination is a potentially safe and effective cancer therapy. However, the clinical results have been variable. Since the elderly are preferentially affected by diseases targeted by DC-directed immunotherapy, it is quite striking that few studies to date have focused on the effect of aging on DC function, a key aspect of optimal immunotherapy design in an aging population. In the present paper, we will discuss the consequences of aging on murine bone marrow-derived DC function and their use in cancer immunotherapy.

/pdf/mechanisms-of-murine-dendritic-cell-antitumor-dysfunction-in-17u0vvpphq.pdf

Mechanisms of murine dendritic cell antitumor dysfunction in aging.

Background: Dendritic cells (DCs) play a major role in cell-mediated immunotherapy. In this approach, DCs are isolated from cancer patients and pulsed with exogenous and specific tumor antigens in vitro, and the antigen-loaded DCs are then transferred to the hosts to enhance the immune response against tumor targets. Clinical observations and animal studies have shown that tumors can elicit immune responses caused by tumor infiltration of T-lymphocytes. Several pilot clinical trials have been recently conducted using this strategy for treating several types of cancers. Objective: To optimize DC-based therapy with emerging molecular imaging techniques. Methods: A review of the most current literature on DCs and imaging work. Results/conclusion: The translational application of DC-based therapy can be supported greatly through molecular imaging. New discoveries on DC migration and behavior in vivo will lead to new advances in the treatment of a broad range of cancers.

Dendritic cells: therapy and imaging

Dendritic Cell-Based Vaccines for Cancer Therapy

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Dendritic Cell-Based Vaccines for Cancer Therapy