Little “Life” Makes Sense (IV) | The Advanced Intelligence Agent of Immunotherapy: Dendritic Cells
Release Date:
2023-09-06 17:37
Introduction to Dendritic Cells
Dendritic cells (DCs) are named for the dendritic processes on their surface, which facilitate antigen capture and communication with other immune cells. Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) in the body, capable of efficiently capturing, processing, and presenting antigens. Immature DCs exhibit robust migratory capacity, whereas mature DCs can effectively activate naïve T cells, serving as the central hub for initiating, regulating, and sustaining immune responses. Under normal conditions, DCs are present in low abundance, accounting for only about 1% of peripheral blood mononuclear cells in humans.
DC Cell Classification
Dendritic cells can be classified into three distinct types.
(1) Conventional dendritic cells (cDCs): a common type of dendritic cell, divided into two major subsets—cDC1 and cDC2. They play a crucial role in antigen capture, processing, and presentation.
(2) Plasmacytoid dendritic cells (pDCs): primarily involved in the production of type I interferons and play a crucial role in antiviral immunity.
(3) Langerhans cells: These cells are distributed in the skin and on its surface and represent one of the earliest dendritic cell types to be identified.
Dendritic cells play a pivotal role in the immune response by activating effector T cells, enhancing cellular immunity, and eliciting humoral immunity. Upon capturing and presenting antigens, dendritic cells can initiate the response of naïve T cells, thereby triggering antigen-specific immune reactions—a critical component of adaptive immunity. Dendritic cells express co-stimulatory molecules that are essential for T-cell activation. They also modulate the nature of the immune response by producing various cytokines, including the establishment of immune tolerance. Furthermore, they are crucial for the formation and maintenance of lymphoid organs, such as the organization of T-cell and B-cell zones in the respiratory tract.
The Interplay Between Dendritic Cells and the Immune System
imDCs: immature dendritic cells; mDCs: mature dendritic cells; DCreg: regulatory dendritic cells; Treg: regulatory T cells; MHC-I, II: major histocompatibility complex class I and II; TCR: T-cell receptor; IL-10: interleukin-10. Red indicates inhibition, blue indicates promotion.
DC cell origin
Dendritic cells originate from hematopoietic stem cells, with two distinct pathways of origin:
(1) Myeloid dendritic cells (MDCs), also referred to as DC1, are derived from myeloid progenitor cells under the stimulation of granulocyte–macrophage colony-stimulating factor (GM-CSF). They share a common precursor with monocytes and granulocytes and include Langerhans cells (LCs), mesenchymal (or dermal) DCs, and monocyte-derived DCs.
(2) Derived from lymphoid progenitor cells, these cells are referred to as lymphoid dendritic cells (LDCs) or plasmacytoid dendritic cells (pDCs; also designated as piX), which correspond to DC2. They share a common precursor with T cells and natural killer (NK) cells. Although dendritic cells constitute less than 1% of peripheral blood mononuclear cells, they express abundant antigen-presenting molecules (MHC class I and MHC class II), co-stimulatory molecules (such as CD80/B7-1, CD86/B7-2, CD40, and CD40L), and adhesion molecules (including ICAM-1, ICAM-2, ICAM-3, LFA-1, and LFA-3), making them highly potent professional antigen-presenting cells (APCs). Dendritic cells possess intrinsic immunostimulatory capacity and are the only APCs capable of activating naïve, unprimed T cells.
Immature DCs exhibit robust migratory capacity, whereas mature DCs can effectively activate naïve T cells, occupying a central role in the initiation, regulation, and maintenance of immune responses. In the human body, the majority of DCs are in an immature state, characterized by low expression of co-stimulatory and adhesion molecules and limited ability to elicit allogeneic mixed lymphocyte proliferation in vitro. However, immature DCs possess exceptional antigen-phagocytic capacity; upon antigen uptake (including ex vivo processing) or exposure to specific stimuli, they differentiate into mature DCs, which, in turn, express high levels of co-stimulatory and adhesion molecules.
During their maturation, DCs migrate from peripheral tissues where they encounter antigens into secondary lymphoid organs, where they interact with T cells and initiate an immune response. As the most potent APC currently known, DCs can induce the generation of antigen-specific cytotoxic T lymphocytes (CTLs). Recent studies have demonstrated that ex vivo pulsing of DCs with tumor-associated antigens or antigenic peptides, followed by reinfusion or immunization of tumor-bearing hosts, can elicit a specific CTL-mediated antitumor immune response.
Dendritic cells (DCs) are closely associated with the initiation and progression of tumors, and in most solid tumors, a higher density of infiltrating DCs is correlated with better patient prognosis. The cornerstone of an effective antitumor immune response is the induction of a cellular immune response dominated by CD8+ T cells, which underpins the use of DCs as an immunotherapeutic modality.
DC Antitumor Mechanism
1. Dendritic cells (DCs) can highly express both MHC class I and MHC class II molecules. These MHC molecules bind to tumor antigens that have been captured and processed by the DCs, forming peptide–MHC complexes, which are then presented to T cells, thereby initiating MHC class I–restricted CTL responses and MHC class II–restricted CD4+ Th1 responses. At the same time, DCs also provide the essential co-stimulatory signals required for T-cell activation through their high expression of co-stimulatory molecules, such as CD80/B7-1, CD86/B7-2, and CD40, thus triggering the immune response.
2. DCs, upon binding to T cells, secrete large amounts of IL-12 and IL-18, which activate T-cell proliferation, induce the generation of cytotoxic T lymphocytes (CTLs), and dominate Th1-type immune responses, thereby facilitating tumor elimination; they also activate perforin–granzyme B– and FasL–Fas–mediated pathways, enhancing NK cell cytotoxicity.
3. Dendritic cells secrete chemotactic cytokines (CCK) that specifically recruit naïve T cells, promoting T-cell aggregation and enhancing T-cell activation. By maintaining effector T cells at the tumor site for an extended period, CCK may influence tumor angiogenesis through the release of certain anti-angiogenic factors (such as IL-12 and IFN-γ) as well as pro-angiogenic factors. Furthermore, CCK activates dendritic cells via positive-feedback paracrine signaling, upregulating the expression of IL-12 and the co-stimulatory molecules CD80 and CD86. At the same time, dendritic cells directly present antigenic peptides to CD8+ T cells; with the assistance of activated CD4+ T cells, this leads to the activation of CD8+ T cells. Moreover, both CD4+ and CD8+ T cells can further enhance the host’s antitumor immune response by secreting cytokines or by direct cytotoxic activity.
Applications of DC Cell Therapy
Dendritic cells not only play a pivotal role in antigen presentation and the activation of immune responses, but also hold promising potential for applications in immune regulation and immunotherapy.
Cancer Immunotherapy: By harvesting dendritic cells from the patient, exposing them ex vivo to tumor-specific antigens, and then reinfusing the modified cells back into the patient, it is possible to elicit a stronger immune response against the tumor, potentially improving cancer treatment outcomes.
Dendritic Cells and Tumor Vaccines: Dendritic cells (DCs) isolated and cultured from peripheral blood are sensitized in vitro, allowing multiple tumor-specific antigens to be presented to the DCs. This activates helper CD4+ T lymphocytes, leading to the generation of antigen-specific memory T cells and antigen-specific CD8+ T lymphocytes that effectively monitor and eliminate early malignant transformation of cancer-initiating cells, thereby inhibiting tumorigenesis at its earliest stages. DC vaccines are safe, easy to administer, and exert immunosuppressive effects against a wide range of tumor types.
Viral therapy: Dendritic cells also hold potential for application in viral therapies, such as the treatment of human immunodeficiency virus (HIV). Researchers are exploring how to harness dendritic cells to stimulate the patient’s immune system and elicit a stronger antiviral immune response.
Treatment of autoimmune diseases: Dendritic cells can be utilized by the body to modulate excessive immune activation, thereby reducing autoimmune damage to normal tissues.
Immune Tolerance in Organ Transplantation: Dendritic cells can be employed to sensitize transplant recipients, inducing immune tolerance to the transplanted organ and thereby reducing the associated immune responses.
Immune monitoring and diagnosis: The state and activity of dendritic cells can reflect the patient’s immune status; therefore, they hold potential as biomarkers for immune monitoring and diagnosis.
In summary, dendritic cells hold great promise for clinical applications in cancer immunotherapy, tumor vaccination, infectious disease treatment, the management of autoimmune disorders, induction of transplant immune tolerance, and immune monitoring and diagnosis. However, several challenges remain, including the efficient preparation and expansion of dendritic cells, consistent therapeutic efficacy, and safety concerns. Researchers are currently investigating strategies to optimize dendritic cell function in order to enhance immune responses and more effectively combat cancer and other diseases.
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