Contrasting functions of CD73 and adenosine in CD8+ T-cell exhaustion during antitumor immunity - PubMed
4 hours ago
- #CD8+ T-cell exhaustion
- #A2AR signaling
- #CD73/adenosine axis
- T-cell exhaustion is a state of functional decline in CD8+ T cells due to chronic antigen exposure and inhibitory signals in the tumor microenvironment.
- Exhausted CD8+ T cells (Tex) originate from precursor exhausted T cells (Tpex), which are self-renewing and crucial for the proliferative response in anti-PD-1 therapies.
- CD73 expression increases during Tpex formation and negatively correlates with Tex generation.
- CD73-deficient OT-I cells (OT-I/CD73KO) show impaired activation and reduced progression to Tex.
- CD73 promotes transcriptional expression of the adenosine receptor A2A (A2AR).
- RNA-seq analysis revealed that exhausted OT-I/CD73KO cells have a more stem-like transcriptomic profile and enriched immune response genes compared to OT-I cells.
- In vivo, cotransfer of naïve OT-I/CD73KO and OT-I CD8+ T cells into tumor-bearing mice increased Tpex frequency among OT-I/CD73KO cells.
- In vitro exhaustion with A2AR agonists decreased Tex frequency and activation/exhaustion markers while increasing CD73 and CD62L (stemness markers).
- A2AR blockade with SYN115 in tumor-bearing mice reduced Tpex markers and increased Tex differentiation.
- CD73 promotes Tpex-to-Tex differentiation, while adenosine A2AR signaling supports Tpex maintenance in the tumor microenvironment.