The Superior Ability of Human BDCA3+ (CD141+) Dendritic Cells (DCs) to Cross-Present Antigens Derived From Necrotic Lung Cancer Cells.

Fei-Fei Gu,Li Liu,Yang-Yang Liu,Jin-Yan Liang,Yu-Lan Zeng,Yue Hu,Kai Zhang,Li-Li Ma,Qi-Fan Yang,Yan Wang,Chang Li

doi:10.3389/fimmu.2020.01267

Abstract

Dendritic cells (DCs) play a key role in initiating and regulating the immune responses to pathogens, self-antigens, and cancers. Human blood DCs comprise a family of different subsets: plasmacytoid DCs (pDCs) and CD16+, CD1c/BDCA1+, and BDCA3+ (CD141+) myeloid DCs and possess different phenotypes and functional characteristics. Lung cancer is the most common cancer, with the highest morbidity and mortality in the world. However, which DC subset plays a leading role in the lung cancer immune responses is unclear. We reanalyzed C-type lectin domain family 9 member A (CLEC9A) and CD141 (THBD) gene expression profiles from the Cancer Genome Atlas (TCGA) database and performed the Kaplan-Meier survival analysis of overall survival for several cancers according to their expression levels. Next, we investigated the capacities of five human blood DC subsets to stimulate T cell proliferation and capture, process and (cross-) present tumor antigen. Human BDCA3+ (CD141+) DCs have a superior capacity to stimulate allogeneic CD4+T cells proliferation and induce superior Th1 response compared with other DC subsets. Interestingly, toll-like receptor (TLR) agonists have little effect on DCs to induce the proliferation of naïve CD4+ T cells, but contribute to their differentiation. Importantly, BDCA3+ (CD141+) DCs possess the most potent ability to cross-present human tumor antigen after their uptake of necrotic lung cancer cells despite their lower antigen uptake. These findings suggest that human BDCA3+ (CD141+) DCs are critical mediators of cytotoxic T lymphocyte responses against EGFR-positive lung cancer. Therefore, our findings may provide theoretical basis for the development of DC-based antitumor vaccines.

Highlights

Lung cancer has recently become the leading cause of cancer-related death worldwide
Low BDCA3+ (CD141+) Dendritic cells (DCs) signature is associated with poor prognosis in lung adenocarcinoma (LUAD), kidney renal papillary cell carcinoma (KIRP), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), head and neck squamous cell carcinoma (HNSC), and skin cutaneous melanoma (SKCM) (Figure 1)
These results show that high BDCA3+ (CD141+) DC signature suggests a better prognosis

Summary

Introduction

Lung cancer has recently become the leading cause of cancer-related death worldwide. In 2015, there were approximately 4.29 million new cancer patients and 2.81 million deaths in China, and the incidence and mortality of lung cancer were ranked first [1]. DCs are the most potent antigen presenting cells (APC) and critical regulators of immune responses. As human blood DCs comprise only 1% of the total PBMC fraction [4], most clinical studies use DCs cultured ex vivo, starting from precursor cells as the basis of immunotherapy vaccines [8]. Monocyte-derived DCs (MoDC) are the most commonly used DC type in DC vaccine formulations [10]. This type of DC vaccine is usually generated by isolating CD14+ monocytes from PBMCs and culturing them in vitro for 6 days into immature DCs with GM-CSF and IL-4. Karolina Palucka et al suggested that the lack of subset specificity in the application of DC vaccines was an important reason for the poor outcome [12]

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Conclusion