The Potential of Dendritic Cell Subsets in the Development of Personalized Immunotherapy for Cancer Treatment

Abstract

Since the discovery of dendritic cells (DCs) in 1973 by Ralph Steinman, a tremendous amount of knowledge regarding these innate immunity cells has been accumulating. Their role in regulating both innate and adaptive immune processes is gradually being uncovered. DCs are proficient antigen-presenting cells capable of activating naive T-lymphocytes to initiate and generate effective anti-tumor responses. Although DC-based immunotherapy has not yielded significant results, the substantial number of ongoing clinical trials underscores the relevance of DC vaccines, particularly as adjunctive therapy or in combination with other treatment options. This review presents an overview of current knowledge regarding human DCs, their classification, and the functions of distinct DC populations. The stepwise process of developing therapeutic DC vaccines to treat oncological diseases is discussed, along with speculation on the potential of combined therapy approaches and the role of DC vaccines in modern immunotherapy.

Keywords: cancer; clinical trials; dendritic cells; immunotherapy; tumor-associated antigen.

Figure 1

The scheme of the ontogenesis of DC populations. Myeloid and lymphoid precursors develop from hematopoietic stem cells. From the myeloid precursor, the macrophage DC progenitor (MDP) develops. The MDP further differentiates into monocytes and AXL⁺ SIGLEC6⁺ cells (AS DCs). AS DCs are capable of giving rise to both pre-DCs and pDC lineages. Pre-DCs are the precursors of cDC1 and cDC2. The pDC population, which originates from the lymphoid precursor, is also considered heterogeneous, with three distinct groups identified: P1-pDC, P2-pDC, P3-pDC.

Figure 2

DCs can be created by various methods in vitro. (A) MoDCs are obtained through directed differentiation from CD14⁺ monocytes using various cytokine combinations, such as IL-4, GM-CSF, IFN-α, IL-15, etc. Resulting cells express several surface markers that are characteristic of moDCs and necessary for antigen presentation [53]. (B) A combination of three main subsets of DCs—cDC1, cDC2, and pDC—can be obtained from HSC CD34⁺ using FMS-like tyrosine kinase 3 ligand (FLT3L), thrombopoietin (TPO), and stem cell factor (SCF). A population similar in marker composition to cDC1 can be obtained through the direct reprogramming of fibroblasts transduced with the transcription factor set PU.1 + IRF8 + BATF3 (PIB) [54]. (C) The process of antigen internalization and DC activation occurs, where the antigens can be tumor vesicles, inactivated tumor cells, or the lysates of tumor cells. Antigen capture occurs, mainly through receptor-mediated phagocytosis mechanisms (lectin-dependent endocytosis, Toll-like receptor endocytosis, and macropinocytosis). One method involves transduction, where the DNA sequence encodes for antigens. An electroporation procedure is used to internalize mRNA molecules. In addition to antigen processing in complex with MHC molecules, a combination of activating molecules serves as a stimulus for maturation under in vitro conditions. The activated (mature) state of DCs is characterized by changes in the expression of costimulatory molecules (CD80, CD86) and integrin and chemokine receptors (CCR7), as well as the suppression of adhesion molecule expression.

Figure 3

The main stages of creating a personalized DC-based vaccine for cancer treatment. Natural DCs, CD14⁺ monocytes, or CD34⁺ are isolated from leukapheresis material. CD14⁺ and CD34⁺ cells are differentiated into immature DCs. For TAA, tumor material is isolated, which can be used to construct the necessary antigen. Mature DCs are obtained using a combination of activating molecules and loading TAA. The ready-made injection consists of mature TAA-activated DCs or vesicles obtained from activated DCs (Dex).