樹状細胞の工学的改変でがん免疫療法を強化(Engineering dendritic cells boosts cancer immunotherapy)

2025-12-18 スイス連邦工科大学ローザンヌ校(EPFL)

Engineered dendritic cells (right) acquire tumor-derived extracellular vesicles that contain cancer antigens (left), stimulating anti-tumor immunity. Credit: EPFL/Ella Maru Studio CC-BY-SA 4.0

<関連情報>

• https://actu.epfl.ch/news/engineering-dendritic-cells-boosts-cancer-immunoth/
• https://www.science.org/doi/10.1126/scitranslmed.adq4060
• https://www.nature.com/articles/s41467-025-64172-w
• https://medibio.tiisys.com/119388/

キメラ抗原受容体による腫瘍抗原の取り込みと樹状細胞の活性化を調整する Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors

Yahya Mohammadzadeh, Vojislav Gligorovski, Olga Egorova, Gabriele Casagrande Raffi, […] , and Michele De Palma
Science Translational Medicine  Published:17 Dec 2025
DOI:https://doi.org/10.1126/scitranslmed.adq4060

Editor’s summary

Dendritic cell (DC)–based therapies for cancer have shown evidence of antitumor immunity but limited efficacy in clinical trials. To improve DC-based therapies, Mohammadzadeh and colleagues developed an inducible DC platform based on an engineered, ubiquitination-resistant instructive chimeric antigen receptor (iCAR) that enables DCs to recognize a molecule present on the surface of tumor cells or extracellular vesicles secreted by tumor cells, promotes DC cell activation to prime antigen-specific T cells through both cross-dressing and cross-presentation, and induces IL-12 expression in response to antigen uptake. In mice carrying immunotherapy-resistant melanoma, iCAR-DCs delayed tumor growth and increased T cell diversity without ex vivo antigen loading or cell maturation, demonstrating proof of concept and supporting further studies of this platform for potential translation. —Melissa L. Norton

Abstract

Effective antitumor immunity requires dendritic cells (DCs) to internalize, process, and present tumor antigens to T cells. Adoptive transfer of DCs that were loaded ex vivo with tumor antigens has been shown to stimulate antitumor immunity in patients with cancer, but clinical responses have been mixed. To address the limitations of traditional DC-based therapies, we constructed and functionally screened a panel of chimeric antigen receptors (CARs) optimized for expression and activity in DCs. Through this screening, we identified key functional components that guided the development of an inducible platform centered on an instructive chimeric antigen receptor (iCAR). This iCAR enabled DCs to (i) recognize a surface molecule present on cancer cells or their extracellular vesicles (EVs), such as disialoganglioside GD2 (expressed in melanoma and other tumors of neuroectodermal origin) or HER2 (expressed in some epithelial cancers), thereby promoting the acquisition of tumor-derived material containing putative tumor antigens; (ii) undergo immunostimulatory activation to prime antigen-specific T cells via both cross-dressing and cross-presentation; and (iii) transactivate the expression of the therapeutic cytokine interleukin-12 (IL-12) in response to antigen uptake. The iCAR converted melanoma-derived EVs from immune-suppressive to stimulatory cues for DCs in cell culture assays. Moreover, systemic administration of iCAR-DCs enhanced antigen-specific T cells, expanded low-frequency T cell clonotypes, and delayed tumor growth in immunotherapy-resistant melanoma models without the need for ex vivo antigen loading or cell maturation. iCAR-DCs may therefore provide a platform for antigen-agnostic cancer immunotherapy that integrates antigen uptake with programmable DC activation.

細胞外小胞内在化受容体を発現するように改変された樹状細胞前駆細胞は、マウスモデルにおける癌免疫療法を強化する Dendritic cell progenitors engineered to express extracellular-vesicle–internalizing receptors enhance cancer immunotherapy in mouse models

Ali Ghasemi,Amaia Martinez-Usatorre,Yang Liu,Hadrien Demagny,Luqing Li,Yahya Mohammadzadeh,Andreas Hurtado,Mehdi Hicham,Linda Henneman,Colin E. J. Pritchard,Daniel E. Speiser,Denis Migliorini & Michele De Palma
Nature Communications  Published:15 October 2025
DOI:https://doi.org/10.1038/s41467-025-64172-w

Abstract

Cancer immunotherapy using dendritic cells (DC) pulsed ex vivo with tumour antigens is considered safe, but its clinical efficacy is generally modest. Here we engineer DC progenitors (DCP), which can replenish conventional type 1 DCs (cDC1) in mice, to constitutively express IL-12 together with a non-signalling chimeric receptor, termed extracellular vesicle-internalizing receptor (EVIR). By binding to a bait molecule (GD2 disialoganglioside) expressed on cancer cells and their EVs, the EVIR enforces EV internalization by cDC1 to promote their cross-dressing with preformed, tumour-derived MHCI-peptide complexes. Upon systemic deployment to mice, the engineered DCPs cause only mild and transient elevation of liver enzymes, acquire tumour-derived material, engage tumour-specific T cells, and enhance the efficacy of PD-1 blockade in an immunotherapy-resistant melanoma model comprising both GD2-positive and -negative cancer cells, without the need for ex vivo antigen pulsing. These results indicate that EVIR-engineered DCPs may avert the positive selection of antigen-negative cancer cells, potentially addressing a critical limitation of immunotherapies targeting defined tumour antigens.