Dendritic cell-based immunotherapy in non-small cell lung cancer: a comprehensive critical review

Abstract

Despite treatment advances through immunotherapies, including anti-PD-1/PD-L1 therapies, the overall prognosis of non-small cell lung cancer (NSCLC) patients remains poor, underscoring the need for novel approaches that offer long-term clinical benefit. This review examined the literature on the subject over the past 20 years to provide an update on the evolving landscape of dendritic cell-based immunotherapy to treat NSCLC, highlighting the crucial role of dendritic cells (DCs) in immune response initiation and regulation. These cells encompass heterogeneous subsets like cDC1s, cDC2s, and pDCs, capable of shaping antigen presentation and influencing T cell activation through the balance between the Th1, Th2, and Th17 profiles and the activation of regulatory T lymphocytes (Treg). The intricate interaction between DC subsets and the high density of intratumoral mature DCs shapes tumor-specific immune responses and impacts therapeutic outcomes. DC-based immunotherapy shows promise in overcoming immune resistance in NSCLC treatment. This article review provides an update on key clinical trial results, forming the basis for future studies to characterize the role of different types of DCs in situ and in combination with different therapies, including DC vaccines.

Keywords: cancer vaccine; checkpoint inhibitors; dendritic cells; immune system; immunotherapy; lung cancer; tumor microenvironment.

Figure 1

Ex vivo and in vivo DC vaccine scheme. In the ex vivo technique, peripheral blood mononuclear cells such as CD14+ monocytes or CD34+ HSPCs are collected from patients by leukapheresis, differentiated into immature DCs in the presence of GM-CSF and IL-4, and then matured in a maturation cocktail consisting of TNF-α, IL-1β, IL-6 and PGE₂, while pulsed with autologous tumor cell lysates or TAAs. Mature DCs loaded with antigen are reinfused into the patient. The in vivo technique is based mainly on radiotherapy and intratumoral injection. For the preparation of intratumoral immunization, there are two divisions: 1) by the mechanism of action which can be divided into pattern recognition receptor (PRR) agonists, ICIs, DCI inducers, tumor antigens, cytokines and others and 2) by the type of preparation which can be divided into pathogens (bacteria, viruses), cells, nucleic acids, proteins (antibodies, small molecule proteins). Radiotherapy induces immunogenic cell death, which is an important step in establishing in situ vaccines. DC, dendritic cells; GM-CSF, granulocytemacrophage colony-stimulating factor; IL-4, interleukin 4; TNF-α, tumor necrosis factor α; PGE₂, prostaglandin E2; HSPCs, hematopoietic stem and progenitor cells; IL-1B, interleukin 1-beta; IL-6, interleukin 6.

Figure 2

Immunomodulatory effects of chemoradiotherapy on immune activation and immunogenic cell death. Schematic representation of the immunogenic cell death cycle, with the release of DAMPs, neoantigens and cytokines from a dying tumor cell, leading to the maturation of a DC and the activation of CD4+ and CD8+ T cells, which in turn trigger the death of the remaining living tumor cells. Combination strategies to maximize the therapeutic efficacy of DC-based immunotherapy and their underlying mechanisms of action. DAMPs, danger-associated molecular patterns; IFN type-I, type-I interferons; MHC I, major histocompatibility complex I; MHC II, major histocompatibility complex II.