Therapy resistance mediated by exosomes

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Abstract

Therapy resistance can arise within tumor cells because of genetic or phenotypic changes (intrinsic resistance), or it can be the result of an interaction with the tumor microenvironment (extrinsic resistance). Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. They transfer therapy resistance by anti-apoptotic signalling, increased DNA-repair or delivering ABC transporters to drug sensitive cells. As functional mediators of tumor-stroma interaction and of epithelial to mesenchymal transition, exosomes also promote environment-mediated therapy resistance.

Exosomes may be used in anticancer therapy exploiting their delivery function. They may effectively transfer anticancer drugs or RNAs in the context of gene therapy reducing immune stimulatory effects of these drugs and hydrophilic qualities facilitating crossing of cell membranes.

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The blockade of immune checkpoints in cancer immunotherapy.

Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

Michael Morse, Jennifer Garst, Takuya Osada … (2005)

Background There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). Methods This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. Results Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. Conclusion Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors

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Bovine milk-derived exosomes for drug delivery.

Radha Munagala, Farrukh Aqil, Jeyaprakash Jeyabalan … (2016)

Exosomes are biological nanovesicles that are involved in cell-cell communication via the functionally-active cargo (such as miRNA, mRNA, DNA and proteins). Because of their nanosize, exosomes are explored as nanodevices for the development of new therapeutic applications. However, bulk, safe and cost-effective production of exosomes is not available. Here, we show that bovine milk can serve as a scalable source of exosomes that can act as a carrier for chemotherapeutic/chemopreventive agents. Drug-loaded exosomes showed significantly higher efficacy compared to free drug in cell culture studies and against lung tumor xenografts in vivo. Moreover, tumor targeting ligands such as folate increased cancer-cell targeting of the exosomes resulting in enhanced tumor reduction. Milk exosomes exhibited cross-species tolerance with no adverse immune and inflammatory response. Thus, we show the versatility of milk exosomes with respect to the cargo it can carry and ability to achieve tumor targetability. This is the first report to identify a biocompatible and cost-effective means of exosomes to enhance oral bioavailability, improve efficacy and safety of drugs.

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Author and article information

Contributors

Ira-Ida Skvortsova:

ORCID: http://orcid.org/0000-0001-8993-611X

++43-512-504-27758 , Ira.Skvortsova@i-med.ac.at

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 30 March 2019

Publication date PMC-release: 30 March 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 58

Affiliations

[1 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Department of Otorhinolaryngology, Head and Neck Surgery, , Medical University of Innsbruck, ; Innsbruck, Austria

[2 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, , Medical University of Innsbruck, ; Anichstr. 35, A-6020 Innsbruck, Austria

[3 ]GRID grid.420164.5, EXTRO-Lab, , Tyrolean Cancer Research Institute, ; Innsbruck, Austria

Author information

Ira-Ida Skvortsova http://orcid.org/0000-0001-8993-611X

Article

Publisher ID: 970

DOI: 10.1186/s12943-019-0970-x

PMC ID: 6441190

PubMed ID: 30925921

SO-VID: 2e4f89ac-fefd-44b3-8295-8bf1ee5a7795

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 November 2018

Date accepted : 21 February 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002428, Austrian Science Fund;

Award ID: P29457

Funded by: FundRef http://dx.doi.org/10.13039/501100004061, Oesterreichische Nationalbank;

Award ID: 17620

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mdr genes,apoptosis,cancer stem cells,immune surveillance,dormancy,emt

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mdr genes, apoptosis, cancer stem cells, immune surveillance, dormancy, emt

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Therapy resistance mediated by exosomes

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Karger: Oncology

Most cited references 79

The blockade of immune checkpoints in cancer immunotherapy.

A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

Bovine milk-derived exosomes for drug delivery.

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Cited by 94

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