Targeted knockdown of the adenosine A2A receptor by lipid NPs rescues the chemotaxis of head and neck cancer memory T cells

• Published in: Molecular therapy. Methods & clinical development Vol. 21; pp. 133 - 143
• Main Authors: Newton, Hannah S., Chimote, Ameet A., Arnold, Michael J., Wise-Draper, Trisha M., Conforti, Laura
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 11-06-2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: Original
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2021.03.001

In solid malignancies, including head and neck squamous cell carcinoma (HNSCC), the immunosuppressive molecule adenosine, which accumulates in the tumor, suppresses cytotoxic CD8+ T cell functions including chemotaxis and tumor infiltration. Adenosine functions through binding to the adenosine A2A receptor (A2AR) present on T cells. In order to increase T cell migration into the tumor, the negative effect of adenosine must be abrogated. Systemic drug treatments targeting A2AR are available; however, they could lead to negative toxicities due to the broad expression of this receptor. Herein, we developed a lipid nanoparticle (NP)-based targeted delivery approach to knock down A2AR in T cells in order to increase their chemotaxis in the presence of adenosine. By using flow cytometry, immunofluorescence, qRT-PCR, and 3D-chemotaxis, we demonstrated that CD45RO-labeled nanoparticles delivering ADORA2A gene-silencing-RNAs decreased ADORA2A mRNA expression and rescued the chemotaxis of HNSCC CD8+ memory T cells. Overall, the data indicate that targeting the adenosine signaling pathway with lipid NPs is successful at suppressing the inhibitory effect of adenosine on the chemotaxis of HNSCC memory T cells, which could ultimately help increase T cell infiltration into the tumor.
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Adenosine in the tumor microenvironment inhibits cytotoxic T cell chemotaxis through adenosine A2A receptor signaling. Conforti and colleagues developed a lipid nanoparticle-based therapeutic, which delivered adenosine A2A receptor-silencing RNAs, knocked down the adenosine A2A receptor, and rescued the chemotaxis of cytotoxic memory T cells in the presence of adenosine.