Dataset Information

Engineered immunomodulatory extracellular vesicles derived from epithelial cells acquire capacity for positive and negative T cell co-stimulation in cancer and autoimmunity.

ABSTRACT: Extracellular vesicles (EVs) are generated by all cells and systemic injection of allogenic EVs derived from epithelial or mesenchymal cells into humans and immunocompetent mice do not elicit any immune response despite the presence of ~1,200 proteins. Nevertheless, EVs from immune cells are purported to play a role in immune regulation associated with cancer and other diseases. To specifically address whether epithelial cells derived EVs can be modified to inherently acquire a capacity to induce immune response, we engineered epithelial 293T EVs to harbor the immunomodulatory CD80, OX40L and PD-L1 molecules. We demonstrated abundant levels of these proteins on the engineered EVs, without causing major morphological and molecular alterations in the donor cells and their shed EVs. Functionally, the engineered EVs efficiently elicit positive and negative T cells co-stimulation in both human and murine T cells ex vivo. The systemic administration of OX40L-containing EVs promotes anti-tumor immunity, whereas PD-L1-containing EVs suppresses T cell-mediated anti-tumor responses. Conversely, OX40L EVs worsen the progression of auto-immune hepatitis, while PD-L1 EVs ameliorate it. Moreover, OX40L EVs synergize with anti-CTLA-4 to delay tumor growth and extend the survival of melanoma-bearing mice. Taken together, our work provides evidence that while epithelial cells derived EVs are immunologically inert when systemically infused in large numbers, the same EVs can be engineered to induce immune response with translational potential to modulate T cell functions in pathological settings.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney Epithelial Cell, Colon Endothelial Cell

DISEASE(S): Melanoma,Colon Adenocarcinoma

SUBMITTER: Sergio Lilla

LAB HEAD: Sara Rossana Zanivan

PROVIDER: PXD044115 | Pride | 2025-05-08

REPOSITORIES: Pride

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			Action	DRS
	20190802_KEH_HF_SA_FEK_EXT_260719_LFQ_exosomes_293human1_009.raw	Raw
	20190802_KEH_HF_SA_FEK_EXT_260719_LFQ_exosomes_293human2_010.raw	Raw
	20190802_KEH_HF_SA_FEK_EXT_260719_LFQ_exosomes_293human3_011.raw	Raw
	20190802_KEH_HF_SA_FEK_EXT_260719_LFQ_exosomes_293human4_012.raw	Raw
	20190802_KEH_HF_SA_FEK_EXT_260719_LFQ_exosomes_WT1_001.raw	Raw

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Publications

Engineered Immunomodulatory Extracellular Vesicles from Epithelial Cells with the Capacity for Stimulation of Innate and Adaptive Immunity in Cancer and Autoimmunity.

Luo Xin X Kugeratski Fernanda G FG Dowlatshahi Dara P DP Sugimoto Hikaru H Arian Kent A KA Fan Yibo Y Huang Li L Wills Danielle D Lilla Sergio S Hodge Kelly K Zanivan Sara R SR LeBleu Valerie S VS McAndrews Kathleen M KM Kalluri Raghu R

ACS nano 20250127 5

Extracellular vesicles (EVs) are generated in all cells. Systemic administration of allogenic EVs derived from epithelial and mesenchymal cells has been shown to be safe, despite carrying an array of functional molecules, including thousands of proteins. To address whether epithelial cell-derived EVs can be modified to acquire the capacity to induce an immune response, we engineered 293T EVs to harbor the immunomodulatory molecules CD80, OX40L, and PD-L1. We demonstrated abundant levels of these ...[more]

PMID: 39869047

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