Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment

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Abstract

<p class="first" id="d1864263e164">Immunotherapy has gained increasing focus in treating pancreatic ductal adenocarcinoma (PDAC), since conventional therapies like chemotherapy could not provide satisfactory improvement in overall survival outcome of PDAC patients. However, it is still not the game changing solution due to the unique tumor microenvironment and low cancer immunogenicity of PDAC. Thus, inducing more intratumoral effector immune cells as well as reversing immunosuppression is the core of PDAC treatment. Herein, we demonstrate an exosome-based dual delivery biosystem for enhancing PDAC immunotherapy as well as reversing tumor immunosuppression of M2-like tumor associated macrophages (M2-TAMs) upon disruption of galectin-9/dectin 1 axis. The deliver system is constructed from bone marrow mesenchymal stem cell (BM-MSC) exosomes, electroporation-loaded galectin-9 siRNA, and surficially modified with oxaliplatin (OXA) prodrug as an immunogenic cell death (ICD)-trigger. The use of biomaterials, BM-MSC exosomes, can significantly improve tumor targeting efficacy, thus increasing drug accumulation in the tumor site. The combined therapy (iEXO-OXA) elicits anti-tumor immunity through tumor-suppressive macrophage polarization, cytotoxic T lymphocytes recruitment and Tregs downregulation, and achieves significant therapeutic efficacy in cancer treatment. </p>

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Most cited references 44

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The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions. The complex biology of immune checkpoint pathways still contains many mysteries, and the full activity spectrum of checkpoint-blocking drugs, used alone or in combination, is currently the subject of intense study. Copyright © 2015 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Title: Biomaterials

Abbreviated Title: Biomaterials

Publisher: Elsevier BV

ISSN (Print): 01429612

Publication date Created: January 2021

Publication date (Print): January 2021

Volume: 268

Page: 120546

Article

DOI: 10.1016/j.biomaterials.2020.120546

PubMed ID: 33253966

SO-VID: cdb6c4ec-6ac2-4e64-bbcc-843bcee53756

License:

https://www.elsevier.com/tdm/userlicense/1.0/

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