Many observations have led to clinical trials designed to investigate the immunological and clinical effects of Ag-pulsed DCs administered as a therapeutic vaccine to patients with cancer.
Although current DC-based vaccination methods are cumbersome and complex, promising preliminary results from clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer suggest that immuno-therapeutic strategies, that take advantage of the unique properties of DCs, may ultimately prove both efficacious and widely applicable treatment in patients with cancer.
Dendritic cells originate from hematopoietic progenitors. Circulating precursors give rise to inmature tissue-residing, atigen-capturing DCs,the differentiation of which is subject to mircroenvironmental regulation.
Following antigen capture and activation by either signals from surrounding cells or pathogen products, DCs migrate to lymphoid organs.Mature antigen-presenting DCs display peptide/MHC complexes and costimulatory molecules, allowing selection, expansion, and differentiation of antigen-specific lymphocytes.
Dendritic cells (DCs) are the crucial cells providing the necessary components for initiating and developing effective cell-mediated immune (CMI) responses. Dendritic cells, located in most tissues of the body, capture and process Ags, which are then displayed as MHC-peptide complexes on the DC surface. Essential co-stimulatory molecules are upregulated on DCs as they migrate to secondary lymphoid organs (the spleen and lymph nodes) where they liaise with na?ve T cells, inducing the activation and proliferation of Ag specific CTLs. Thus, effective DC function in cancer involves several interlinked biological processes that occur in following sequence:
DENDRITIC CELLS AND CANCER
Escape from immune surveillance is believed to be a fundamental biological feature of malignant disease in man, which contributes to uncontrolled tumour growth, eventually leading to death of the host. Defects in immune response in patients with a variety of tumours have been well documented. These defects have been ascribed mostly to suppressor cell function. Some authors have shown defective function of macrophages in malignant disease. In recent studies, it has been shown that a distinct subset of IA+ epidermal APCs appear capable of inducing tolerance to tumour Ags and that activated macrophages may induce structural abnormalities of the TCR-CD3 complex.
Future clinical trials with dendritic cells pulsed with tumor epitopes derived from newly identified tumor-associated peptides, RNA, lystates, and apoptotic bodies. Dendritic cells might also be genetically modified with cDNA encoding.
Some studies in humans with solid cancers have investigated DC trafficking in peripheral blood. It was showed that DCs in the peripheral blood of patients with head and neck cancer were significantly immunosuppressed.
There was also an increased intratumoural presence of the immunosuppressive CD34+ progenitor cells. Patients with head and neck squamous cell carcinoma also had increased levels of the immunosuppressive peripheral blood CD34+ cells.
Defects in response to tetanus toxoid and influenza virus were observed in patients with advanced breast cancer. Dendritic cells isolated from patients with breast cancer demonstrated a significantly decreased ability to stimulate control allogeneic T cells.Data suggest that reduced DC function could be a major cause for the observed defect in cellular immunity documented in the patients with breast cancer.
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