Dendritic Cell-Based Cancer Vaccines: The Impact of Modulating Innate Lymphoid Cells on Anti-Tumor Efficacy

Abstract

Dendritic cell (DC) vaccines stimulate the immune system to target cancer antigens, representing a promising option for immunotherapy. However, clinical trials have demonstrated limited effectiveness, emphasizing the need for enhanced immune responses. Improving the production of DC vaccines, assessing their impact on immune components, and observing responses could improve the results of DC-based therapies. Innate lymphoid cells (ILCs) represent a heterogeneous population of innate immune components that generate cytokines and modulate the immune system, potentially enhancing immunotherapies. Recent research highlights the different functions of ILCs in cancer, demonstrating their dual capabilities to promote tumors and exhibit anti-tumor actions. DCs and ILCs actively communicate under physiological and pathological conditions, and the activation of ILCs by DCs or DC vaccines has been shown to influence ILC cytokine production and function. Gaining insights into the interaction between DC-activated ILCs and tumors is essential for creating exciting new therapeutic strategies. These strategies aim to boost anti-tumor immunity while reducing the support that tumors receive. This review examines the effect of DC vaccination on host ILCs, illustrating the complex relationship between DC-based vaccines and ILCs. Furthermore, it explores some exciting strategies to enhance DC vaccines, aiming to boost anti-tumor immune responses by fostering better engagement with ILCs.

Keywords: dendritic cell (DC) vaccines; innate lymphoid cells (ILCs); tumor microenvironment (TME).

Figure 2

Anti-Tumor Roles of ILCs in the Tumor Microenvironment (TME). Under specific conditions, ILC subsets contribute to anti-tumor immune responses. ILC1s support tumor suppression through Granzyme B-mediated cytotoxicity in a breast cancer model, and CXCR6-dependent tumor control occurs in hepatic metastasis [164,165,166]. ILC2s display tumor-type–specific functions across distinct cancer models. In lymphoma, they secrete IL-10 and promote IL-33 expression, which drives CXCR2 and its ligands, contributing to tumor cell apoptosis. In CRC, ILC2s enhance anti-tumor immunity by activating CD8⁺ T cells. In melanoma, they produce IL-5, which facilitates the recruitment of eosinophils into the TME and supports immune-mediated tumor control [147,149,152]. ILC3s exert TRAIL-dependent cytotoxicity, particularly in hepatocellular carcinoma and melanoma, and promote tumor suppression by releasing effector cytokines, including IFN-γ, GM-CSF, IL-8, IL-22, and TNF-α [162].

Figure 3

Pro-Tumor Functions of ILCs in the TME. ILCs contribute to tumor progression and immune evasion. ILC1s in NSCLC reduce cytotoxicity and impair IFN-γ production. IL-12/IL-18 signaling contributes to diminished responsiveness and effector function [127]. ILC2s secrete IL-13, IL-4, and amphiregulin, contributing to tumor-associated immune suppression [134,135,136,140,167]. In breast cancer models, IL-33 and IL-13 signaling promote the expansion of Tregs and MDSCs, thereby facilitating tumor progression [146]. ILC3 in breast cancer secretes CXCL13 and CCL21, promoting stromal interactions and tumor-associated inflammation, contributing to tumor progression and metastasis [151,160,168,169,170].

Figure 1

The standard procedure for generating DC vaccines.

Figure 4

DC–ILCs Crosstalk in Homeostasis and Cancer Immunotherapy. Illustration of the multifaceted interactions between DCs and ILCs. Upon activation, DCs release cytokines such as IL-12, IL-15, and IL-18, which stimulate ILC1s and NK cells to produce IFN-γ and TNF-α, thereby promoting cytotoxic and anti-tumor responses. ILC2s, influenced by IL-13 and TL1A, support Th2-mediated immunity [187]. ILC3s, activated via CD226 (DNAM-1) signaling, secrete IL-17, enhancing T cell activation. Additionally, ILC3s activated by IL-23 and IL-1β produce CXCL10, which stimulates CD8⁺ and CD4⁺ T cells, contributing to tumor suppression [178,195]. DC-based cancer vaccines activate cDC1s, which release IL-12 and type I IFNs, driving ILC1 differentiation and enhancing cytotoxic T-cell responses. NK cells further enhance vaccine efficacy by amplifying anti-tumor immunity [194]. ILC2s and MDSCs promote T cell suppression, potentially reducing vaccine effectiveness [107]. ILC3s, stimulated by DC-derived signals, are reprogrammed toward a more anti-tumor NCR⁺ phenotype. These NCR⁺ ILC3s express T-bet, promoting Th1-like immune responses [11,195].

Figure 5

Strategic Enhancements of DC Vaccines through Targeting ILCs. DC-based cancer vaccines can be optimized by utilizing ILCs interactions. IL-12 and IL-18, secreted by engineered DCs, stimulate NK cells, which enhance cytotoxicity, support CTL expansion within the TME, and recruit additional DCs [200]. Engineered DC vaccines further enhance ILC1 expansion within the TME. Additionally, IL-33 activation of ILC2/ILC3 modulates the TME. DCs engineered to express co-stimulatory molecules (CD80/CD86) strengthen interactions with ILC2s and ILC3s, promoting cytokine secretion and effector activation [209]. Modified DC vaccines facilitate the recruitment of ILC3s, which secrete IL-22 and IL-17, contributing to a pro-inflammatory response in the TME [211]. ILC3s, in turn, release Granzyme B and IFN-γ, enhancing tumor suppression through cytotoxic activity, immune cell recruitment, and apoptosis induction [113,180].