Efficacy of Using Dendritic Cells in the Treatment of Prostate Cancer: A Systematic Review

Abstract

(1) The primary prostate cancer treatment involves androgen deprivation therapy, with or without chemotherapy. Immunotherapy has emerged as a promising strategy against cancer due to its ability to modulate the immune system, overcome immune evasion, and stimulate the attack on tumor cells. Thus, this review urges an exploration of the underlying mechanisms to validate the efficacy and safety of dendritic cell immunotherapy for prostate cancer treatment. (2) An extensive literature search identified 45 eligible studies in PubMed, Web of Science, SCOPUS, and Embase databases. Phase I and II clinical trials and in vitro studies (PROSPERO registration number CRD42024538296) were analyzed to extract information on patient selection, vaccine preparation, treatment details, and disease progression. (3) Despite significant variability in vaccine development and treatment protocols, vaccines were shown to induce satisfactory immune responses, including T-cell activation, increased CD4 and CD8 cell populations, upregulated expression of HLA-A2 and HLA-DR, enhanced migratory capacity of dendritic cells, and elevated interferon levels. Cytokine responses, particularly involving Interleukin 10 (IL-10) and Interleukin 12 (IL-12), varied across studies. Immunotherapy demonstrated potential by eliciting positive immune responses, reducing PSA levels, and showing an acceptable safety profile. However, side effects such as erythema and fever were observed. (4) The analyzed treatments were well-tolerated, but variability in clinical responses and side effects underscores the need for further research to optimize the efficacy and safety of this therapeutic approach.

Keywords: cancer; immune response; immunotherapy; lymphocytes; vaccine.

Figure 1

PRISMA flow diagram. Results of the bibliographic search. From [17].

Figure 2

Main studied characteristics. (A) Types of studies; (B) inclusion criteria of the patients. PSA—Prostate specific antigen.

Figure 3

Main characteristics of the included studies. (A) Data on the dendritic cells’ differentiation, maturation, and harvesting. (B) Immunotherapy details: treatment routes, time, and doses. GM-CSF—Granulocyte-Macrophage Colony-Stimulating Factor; IL—Interleukin; LPS—Lipopolysaccharide; DCPM—Dendritic Cell Propagation Medium; TNF-α—Tumor Necrosis Factor α; IFN-γ—Interferon γ; PGE—Prostaglandin; KLH—Keyhole Limpet Hemocyanin.

Figure 4

Risk of bias summary. (A) Methodology quality indicators for each included study (the review team’s judgments on each domain of risk of bias) at the level of the individual study. (B) All studies that evaluated dendritic cell immunotherapy for the treatment of prostate cancer. The Cochrane risk of bias tool was based on whether specific outcomes were marked as low risk of bias, high risk of bias, or ‘unclear risk’ (the item was not reported), resulting in an unknown risk of bias. Assessing Risk of Bias in a Randomized Trial. From [18].

Figure 5

The figure represents the influence of dendritic cells in the tumor environment and how they act in controlling tumor progression. In the tumor environment, inflammatory cytokines are produced, which will either maintain chronic inflammation through the expression of CXCL1/CXCL2 or act on neighboring cells through TNF-α, IFN-γ, and IL-17 which will reprogram these cells, favoring tumor progression. The protective/immunogenic effect of dendritic cells, in turn, will stimulate NK cells to secrete interferon, which sensitizes tumor cells to T cells, which were activated by dendritic cells. Green arrow—increase in expression/production.

Figure 6

(A) Activation of T cells by dendritic cells in lymph nodes; (B) binding of T cells to tumor cells inducing apoptosis; (C) signaling pathways for activation of cell growth and proliferation or signaling pathways for cycle arrest or apoptosis. Pathway 1—The binding of IFN-γ to the INF-γ receptor activates the JAK-STAT signaling cascade. Dysfunctional IFN-1 signaling is directly related to determining the characteristics of the immune inflammatory environment of PCa. However, phosphatase and tensin homolog (PTEN) antagonize the pro-growth PI3K signaling pathway of PCa mediated through the ARF–MDM2–p53 axis. Pathway 2—Granzymes and perforin are packaged into cytotoxic T lymphocytes and natural killer (NK) cells. When cells bind to target cells, these proteins are released where perforin mediates the influx of granzymes through the formation of pores in the target cell membrane. The granzyme causes increased production of reactive oxygen species and release of cytochrome C by mitochondria, which activate caspase-dependent apoptotic pathways including Cas3 and Cas8. Pathway 3—Tumor recognition leads to activation of T cells and upregulation of Fas and FasL on the surface of T cells, activating the Cas8.3 cascade and ultimately apoptosis; pathway 4—TNFR1 initiates an extracellular signal by binding to “death receptors”. FAS and TRAIL are examples of these messengers that trigger the extrinsic apoptosis pathway; they bind to the TRAILR or FASR receptors, causing changes in the intracellular domain of the receptor. With these alterations, an intracellular protein FADD (Fas-associated death domain protein) is activated. It then interacts with two additional proteins, pro-caspase-8 and pro-caspase-10, which initiate the process of cell death. Pathway 5—Acetyl-L-Carnitine (ALCAR) prevents the synthesis of pro-inflammatory chemokines and TNF-α and IFN-γ, leading to a reduction in invasion, proliferation, and migration.