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Single-Cell RNA Editing Identifies T Cell ADAR1 as a Key Regulator of Immune Exhaustion and Anti-PD-1 Resistance in
Da Kang1,2, Song-Zuo Xie2,3, Yong-Zhou Luo2,4
1Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, P. R. China.
Abstract:
ADAR1-mediated RNA editing has been implicated in tumor immune evasion, primarily through tumor-intrinsic interferon (IFN) signaling. However, its cell-type-specific roles within immune compartments, particularly T cells, remain unclear in colorectal cancer (CRC). RNA editing landscapes were profiled using bulk RNA sequencing and full-length single-cell RNA sequencing. ADAR1 expression and RNA editing activity were analyzed across the tumor microenvironment (TME), followed by functional validation and multi-cohort clinical evaluation. Single-cell analyses revealed elevated ADAR1 activity in tumor-infiltrating T cells, defining an exhausted and proliferative T cell state associated with immune dysfunction. Functional experiments demonstrated that ADAR1 promotes T-cell exhaustion and impairs cytotoxic activity. In vivo adoptive transfer models further confirmed that ADAR1 overexpression in T cells limits antitumor efficacy. Mechanistically, ADAR1 activated the TGF-β-SMAD signaling pathway. Clinically, elevated ADAR1 expression in T cells was associated with reduced response to anti-PD-1 therapy across immunotherapy cohorts. These findings identify ADAR1 as a key regulator of dysfunctional T cell states in CRC and suggest that targeting ADAR1 activity in T cells may represent a promising strategy for improving immunotherapy efficacy and developing predictive biomarkers.
Insights
ADAR1 RNA editing in colorectal cancer T cells drives exhaustion and impairs anti-tumor immunity. Targeting ADAR1 in T cells may enhance immunotherapy response and serve as a predictive biomarker.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- ADAR1-mediated RNA editing is linked to tumor immune evasion via interferon signaling.
- The specific role of ADAR1 in T cells within the colorectal cancer tumor microenvironment is not well understood.
Purpose of the Study:
- To investigate the cell-type-specific roles of ADAR1 in T cells within colorectal cancer.
- To determine the impact of ADAR1 on T cell function, antitumor immunity, and response to immunotherapy.
Main Methods:
- RNA editing landscapes were profiled using bulk and single-cell RNA sequencing.
- ADAR1 expression and activity were analyzed in the tumor microenvironment.
- Functional experiments and in vivo models assessed ADAR1's impact on T cell function and antitumor efficacy.
- Clinical cohorts were evaluated for associations between ADAR1 expression and immunotherapy response.
Main Results:
- Elevated ADAR1 activity was observed in tumor-infiltrating T cells, correlating with an exhausted and dysfunctional state.
- ADAR1 was found to promote T cell exhaustion, impair cytotoxic activity, and limit antitumor efficacy in vivo.
- ADAR1 activation of the TGF-β-SMAD signaling pathway was identified as a key mechanism.
- High ADAR1 expression in T cells predicted reduced response to anti-PD-1 therapy.
Conclusions:
- ADAR1 is a critical regulator of T cell dysfunction in colorectal cancer.
- Targeting ADAR1 in T cells presents a potential strategy to enhance immunotherapy efficacy.
- ADAR1 expression in T cells may serve as a predictive biomarker for immunotherapy response.
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