Abstract 95P
Background
ADAR1, as an RNA editing writer, has been extensively studied in various tumors due to its strong correlation with the interferon response (IFN) pathway. However, its role in immune cells remains unclear. This study investigated the potential biological functions of ADAR1 across different cell types, providing new insights into immune therapy resistance and the potential of targeting ADAR1 expression in T cells for colorectal cancer (CRC) immunotherapy.
Methods
RNA editing profiles from single-cell and bulk transcriptome sequencing data were obtained through a series of bioinformatics workflows. Subsequent data analyses, including gene enrichment, NMF clustering, linear correlation, RNA stability, and single-cell related analyses, were conducted to explore the potential roles of ADAR1 in CRC cell subtypes. Experiments such as flow cytometry (FC), ELISA, xenograft models, immunohistochemistry (IHC), and immunofluorescence (IF) were used to investigate the negative regulation of the immune response by ADAR1 expression in T cells.
Results
Adenosine-to-inosine (A-to-I) editing events exhibited variations in different cell types, suggesting that ADAR1 contributed to the intra-tumor heterogeneity in CRC (4 clusters in editing profiles). Further bioinformatics analysis indicated that T cells, rather than epithelial cells, were the primary source of ADAR1 in CRC tissue (EGA, GEO datasets). ADAR1 expression was associated with the negative regulation of immune response signaling, and clinical data revealed that patients with higher ADAR1 levels in T cells benefited less from immunotherapy (pCR : non-pCR = 0.4 : 1.2). Experimental data from human samples showed that ADAR1 promoted T cell exhaustion and reduced cytotoxic activity against tumor tissues (Increase of exhausted markers in FC: 7% PDCD1, 19% TIGIT, 29% LAG3).
Conclusions
Our study firstly identified T cells as the primary contributors to ADAR1 expression in CRC tissues, shifting the focus of immunosuppressive effects from epitheliums to immune cells. This finding suggested new treatment strategies for immunotherapy targeting ADAR1 in T cells.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Guangdong Basic and Applied Basic Research Foundation (Grant No. 2023A1515010243).
Disclosure
All authors have declared no conflicts of interest.