Abstract:
:It was previously demonstrated that engineered mesenchymal stem cells (MSCs) which express a high level of a very efficient modified gene CYP2B6* (CYP2B6TM-RED) acting as a suicide gene (MSC-2B6*) in combination with cyclophosphamide (CPA) constitute a powerful cell/gene therapy approach for solid tumors. In murine models, this combination led to tumor eradication and triggered a durable immune response against tumoral cells, which prevented recurrence and metastasis. The first goal, in this work, was to determine whether the mechanism of tumor cell death caused by CPA metabolites could explain the appearance of this anti-tumor immune response. In vitro, CPA metabolites produced by MSC-2B6* were able to induce immunogenic cell death (ICD) of tumor cells. Indeed, all ICD characteristic events were clearly identified: calreticulin translocation, LC3II expression and release of ATP and HMGB1. The second goal was to determine the respective roles of the direct cytotoxicity of CPA metabolites and the immune anti-tumor response due to ICD of tumor cells during tumor eradication. In vivo, the early inhibition of ICD (with anti-HMGB1 antibodies) or the depletion of CD8+T lymphocytes (with anti-CD8 antibodies) prevented tumor eradication by CPA metabolites and tumor regrowth occurred, despite CPA treatment. In conclusion, the full eradication of the tumors depends on the association of cytotoxic CPA metabolites triggering the ICD of tumor cells and an anti-tumor immune response. The absence of one or the other of these effects prevents the complete eradication of tumors.
journal_name
Oncoimmunologyjournal_title
Oncoimmunologyauthors
Nayagom B,Amara I,Habiballah M,Amrouche F,Beaune P,de Waziers Idoi
10.1080/2162402X.2019.1667743subject
Has Abstractpub_date
2019-09-27 00:00:00pages
e1667743issue
12eissn
2162-4011issn
2162-402Xpii
1667743journal_volume
8pub_type
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