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Harnessing Notch Signaling to Enhance the Generation and Functionality of Human Conventional Type I Dendritic Cells for Cancer Immunotherapy Applications

ABSTRACT: Conventional dendritic cell type I (cDC1) are essential for an effective antitumor immune response, and their presence in the tumor microenvironment is positively correlated with clinical benefits. The extremely low frequency of these cell subsets in peripheral blood limits their application as a cellular vaccine for cancer immunotherapy. Developing a robust in vitro culture system for their large-scale generation from hematopoietic stem cells (HSCs) is a potential approach for generating cDC1-based cellular vaccines. We have developed a novel culture system by exploiting the Notch signaling requirement for cDC1 differentiation from HSCs and successfully generated billions of cDC1s from every million input CD34+ cells. We compared the gene expression profiles of cDC1s generated under feeder-free conditions or on feeders with or without Notch ligands using bulk RNA sequencing. Our results confirm that the in vitro-generated cDC1s are bona fide cDC1s and closely resemble naturally circulating cDC1s in vivo. The cDC1 generation system represents a significant opportunity to develop novel cellular vaccines for cancer immunotherapy, leveraging cross-presenting DC subsets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273410 | GEO | 2025/06/17

REPOSITORIES: GEO

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Project description:Tumors and chronic infections result in sustained antigen exposure, which promotes impaired functional responsiveness in T cells referred to as exhaustion. Checkpoint immunotherapy can induce the reinvigoration of cellular immunity by activating a recently identified precursor of exhausted T (TPEX) cell population. This activation requires cellular interactions between TPEX cells and professional antigen-presenting cells, likely conventional dendritic cells (cDC). Currently, it is unknown where cDC - TPEX cell interactions take place and which cDC subsets are involved. To address these questions, we first mapped the differentiation trajectory of TPEX cell subsets via transitory cellular states towards terminally exhausted T (TEX) cells, identified transcriptionally distinct subpopulations and defined their localization in the spleen during chronic viral infection. We found that cDC were required for TPEX cell proliferation, differentiation and viral control during PD-L1 treatment. In particular cDC1, a specialized subset of dendritic cells, colocalized with TPEX cells and regulated their maintenance by promoting the functionality of stromal cells that support TPEX cell survival. Additionally, during PD-L1 treatment, the splenic cDC1 network was significantly reorganized at the marginal zone, a site of TPEX cell differentiation. As a consequence, viral control during checkpoint immunotherapy and cellular integrity of the marginal zone depended on the presence of cDC1. Since cDC2 were sufficient to drive initial TPEX cell proliferation and TEX cell generation but not viral control, our data suggest a new concept in which cDC1 decelerate the speed of differentiation of TPEX cells via transitory cellular states and thereby generate a therapeutic window for effective immunotherapy. Together, our findings reveal how the dynamic spatial organization of the DC network supports cellular niches that guide the maintenance and differentiation of TPEX cells and opens new avenues to optimize checkpoint immunotherapy.

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Harnessing Notch Signaling to Enhance the Generation and Functionality of Human Conventional Type I Dendritic Cells for Cancer Immunotherapy Applications

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