API

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Relationship: 3533

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, AhR leads to Over-expression of PD-L1 in cancer cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Activation, AhR
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Over-expression of PD-L1 in cancer cells

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
AhR activation leading to cancer progression via immunosuppression adjacent Léo SPORTES-MILOT (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

An increase in AHR activity in both immune cells and tumor cells is linked with a higher expression of PD-L1 (Fang et al., 2021; Jiang et al., 2024).

Numerous studies have shown that the activation of AHR by its ligands, such as TCDD or kynurenine, can be linked to an overexpression of PD1 (Liu et al., 2018; Helou et al., 2023) and PD-L1 in cancer cells (Kenison et al., 2021; Han et al., 2023; Snyder et al., 2025). Also, Han et al. (2023) demonstrated by chromatin immunoprecipitation (ChIP) that AHR binds to the PD-L1 promoter and controls its transcription in non-small cell lung cancer (NSCLC) (Han et al., 2023).

A study also observed a self-activation loop of the AHR signaling pathway through IDO1 and kynurenine; thus, IDO1 is also a key element in the activation of AHR and, consequently, the overexpression of PD-L1 in cancer cells (Snyder et al., 2025). Amobi-McCloud et al. (2021) demonstrated an increase in IDO1 expression in tumor-infiltrating CTLs, macrophages, and non-cancer cells from mouse ovarian cancer. With results showing an increase in the PD1+ cells measured by cell cytometry in T lymphocytes, the authors conclude an activation of the PD1/PD-L1 axis mediated by the AHR pathway through the increase of IDO1 expression (Amobi-McCloud et al., 2021).

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

Amobi-McCloud, A., Muthuswamy, R., Battaglia, S. et al. (2021). IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation. Front Immunol 12, 678999. https://doi.org/10.3389/fimmu.2021.678999.

Fang, W., Zhou, T., Shi, H. et al. (2021). Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8+ T cell exclusion. J Exp Clin Cancer Res 40, 4. https://doi.org/10.1186/s13046-020-01786-6.

Han, S.-C., Wang, G.-Z., Yang, Y.-N. et al. (2023). Nuclear AhR and membranous PD-L1 in predicting response of non-small cell lung cancer to PD-1 blockade. Signal Transduct Target Ther 8, 191. https://doi.org/10.1038/s41392-023-01416-5.

Helou, D. G., Quach, C., Fung, M. et al. (2023). Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells. J Allergy Clin Immunol 151, 526-538.e8. https://doi.org/10.1016/j.jaci.2022.07.022.

Jiang, X., Wang, J., Lin, L. et al. (2024). Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity. Signal Transduct Target Ther 9, 352. https://doi.org/10.1038/s41392-024-02042-5.

Kenison, J. E., Wang, Z., Yang, K. et al. (2021). The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation. Proc Natl Acad Sci U S A 118, e2012692118. https://doi.org/10.1073/pnas.2012692118.

Liu, Y., Liang, X., Dong, W. et al. (2018). Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation. Cancer Cell 33, 480-494.e7. https://doi.org/10.1016/j.ccell.2018.02.005.

Snyder, M., Wang, Z., Lara, B. et al. (2025). The aryl hydrocarbon receptor controls IFN-γ-induced immune checkpoints PD-L1 and IDO via the JAK/STAT pathway in lung adenocarcinoma. J Immunol, vkae023. https://doi.org/10.1093/jimmun/vkae023.