Abstract
BackgroundPrevious studies have reported the potential of aryl hydrocarbon receptor (AhR) in cancer immunotherapy. However, the mechanisms underpinning its therapeutic value have yet to be comprehensively investigated. Thus, this research aimed to explore the underlying association between AhR and cancer immunotherapy in 33 human cancers.MethodsThe gene expression data and clinical characteristics of 33 cancers were retrieved from The Cancer Genome Atlas database. The immunotherapeutic cohorts included GSE67501 and GSE78220 as well as IMvigor210, which were obtained from the Gene Expression Omnibus database and included in a previously published study respectively. Clinical parameters, including patient age, gender, survival, and tumor stage were analyzed to assess the prognostic value of AhR. The activity of AhR was generated by single sample gene set enrichment analysis and used to evaluate the difference between the AhR transcriptome and protein expression level. To better understand the role of AhR in cancer immunotherapy, the correlation between AhR and tumor microenvironment, as well as its relation to immune processes/elements, such as immune cell infiltration, immune inhibitors and stimulators, and the major histocompatibility complex were analyzed. The relevant underlying pathways associated with AhR signaling in cancer were also explored. Furthermore, the correlation between AhR and two immunotherapeutic biomarkers (tumor mutational burden and microsatellite instability) was investigated. Finally, the relationship between AhR and immunotherapeutic response was explored using three independent immunotherapeutic cohorts.ResultsAlthough AhR was not closely associated with age (5/33), gender (3/33), or tumor stage (3/21) in any of the studied human cancers, it exhibited potential prognostic value for predicting patient survival. Consistency has been observed between AhR activity and expression in some cancers (7/33). Generally, AhR presented a robust correlation with immune cell infiltration, immune modulators, and immunotherapeutic markers. Moreover, high AhR expression was significantly related to immune-relevant pathways. However, no significant correlation was observed between AhR and the immunotherapeutic response.ConclusionsThis research investigated the immunotherapeutic value of AhR in 33 human cancers, providing evidence regarding the function of AhR and its role in clinical treatment. However, considering that a bioinformatics approach was adopted, the current results are preliminary and require further validation.
Highlights
The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and transcription factor that is mainly activated by its cognate ligand [1]
AhR was differentially highly expressed among elder patients of the CHOL, PRAD, and THYM groups, whereas it was weakly expressed in ESCA and THCA cases (Figure 2B)
AhR expression was significantly correlated with tumor stage of some cancers, including BLCA, KIRP, and STAD (Figure 2C)
Summary
The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and transcription factor that is mainly activated by its cognate ligand [1] This receptor garnered attention because of its crucial role in mitigating the toxic effects of environmental pollutants [1]. AhR belongs to the basic helix-loop-helix/PERARNT-SIM transcription factor family and was first studied as a receptor for the exogenous ligand 2, 3, 7, 8-tetrachlorodibenzo-pdioxin [2]. It is distributed in almost all human tissues and is highly expressed in the placenta, liver, and the lungs [3]. This research aimed to explore the underlying association between AhR and cancer immunotherapy in 33 human cancers
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