PERSONALIZED MEDICINE - Exploring the Potential of the Aryl Hydrocarbon Receptor for Personalized Medicine

INTRODUCTION

Personalized medicine approaches hold much promise as the future standard of care, and the aryl hydrocarbon receptor (AhR) is gaining traction as a tool for customizing therapies for both cancers and infectious diseases. Recent scientific findings have highlighted the significance of this transcription factor in im­mune regulation, tumor development, and therapy response. However, a comprehensive understanding of the AhR’s drug re­sponse is necessary to develop tailored therapeutics. The follow­ing article emphasizes the intricacies of AhR immune sensing and signaling, and its potential for personalized treatment strategies to optimize therapeutic outcomes and minimize adverse effects. It will also touch on some of the limitations hindering the ad­vancement of knowledge in this crucial area of research, and the direction this emerging field may take in the coming years.

UNVEILING THE FUNCTION OF THE AHR

A complex interplay of numerous factors – such as the envi­ronment, microbiota, infection, diet, stress, and metabolism – af­fect our health and response to disease. The body’s cells are continually exposed to both external and internal stimuli, and so must be able to adapt quickly to maintain homeostasis. Multiple cellular sensors have been shown to respond to changes in the cellular microenvironment, including the AhR, a protein that has long intrigued immunologists due to its diverse roles in immune regulation. The AhR is a ligand-activated transcription factor able to detect a wide range of molecular cues, such as those originating from the environment, diet, disease, and drugs. It translates this information into highly specific cellular responses tailored to each ligand, cell, and tissue type, eliciting the actions necessary for the maintenance of homeostasis.

Notably, the AhR has been reported to be a convergence point for several signaling pathways inside the cell, including those regulating inflammation, immunity, cell proliferation and differentiation, cell morphology, cell adhesion, and cell migration. As a result, its activities are known to be implicated in the body’s responses to a range of inflammatory disorders, microbial infec­tion, and cancer. Interestingly, the receptor acts as a sensor for a variety of disease mechanisms and modulates the way the body processes and reacts to therapeutic drugs, indicating it may have a profound impact on treatment efficacy. It is hoped that, by fine-tuning the AhR’s activity, the mechanism of action of many ther­apeutics can be improved, potentially enabling personalized medicine and enhancing treatment success for a wide range of health conditions.

ADDRESSING A WIDE KNOWLEDGE GAP

Current understanding of the molecular mechanisms and pathways involved in these AhR-drug interactions is still incom­plete, sparking researchers at the Institute for Research and In­novation in Health (i3S) in Porto, Portugal, to explore this promising receptor further. The institute’s Immune Sensing and Signaling Dynamics Group is dedicated to unraveling the com­plex intracellular network of pattern recognition receptors (PRRs) and signaling pathways triggered in different cell microenvironments as part of the human body’s im­mune response. It also investigates how this network affects, and is itself impacted by, AhR-elicited responses.

The group is dissecting AhR’s compli­cated feedback loop to better understand how it senses and shapes the microenvi­ronment, and how it modulates different cellular and tissue responses. The team aims to assess how AhR modulation im­pacts therapy efficacy, with the ultimate goal of establishing the potential of AhR manipulation in personalizing treatments for cancers and bacterial infections. The group’s research therefore focuses prima­rily on three main areas: host-pathogen interactions, host-tumor interactions, and host-drug interactions, with mice and ze­brafish being the initial model systems of choice for this exciting work.

OVERCOMING HURDLES TO DISCOVERY

The Immune Sensing and Signaling Dynamics Group’s work includes screen­ing panels of drugs that have already been clinically approved for other disease indi­cations. On a typical day, each person within the group will process six or seven cell culture plates, changing the media in each plate several times a week. This in­volves the painstaking removal of excess liquid from each individual well without disturbing the cells, which is extremely time consuming and error prone. Although vacuum aspiration systems are available to aid this task, many of these instruments do not have adjustable speed settings, and so aspirate too quickly by default. This means the precious cells are often dis­turbed – or entirely removed from the wells along with the waste liquids – negating the team’s hard work and significant time in­vestment, as well as affecting the reliability of results and hindering the group’s pro­ductivity. On top of these challenges, in­consistent pipetting of samples into wells has historically affected the accuracy and reproducibility of the team’s end results, further frustrating the lab’s progress and leading to repeat testing, taking up valu­able additional lab time and resources.

These workflow challenges motivated the lab to search for alternative labware solutions. The team chose a VACUSAFE aspiration system and PIPETBOY pipette controller from INTEGRA Biosciences to help solve these common aspirating and pipetting issues and streamline its cell cul­ture workflows. The VACUSAFE is renowned for its precision and efficiency and has contributed significantly to the group’s ability to maintain optimal exper­imental conditions, which is essential for many of the lab’s reporter systems. The device allows users to easily regulate the speed of aspiration for the gentle handling of fragile cell cultures. It also enables them to simultaneously and precisely aspirate liquid from eight wells at a time, rather than one by one, saving valuable hands-on time and reducing the likelihood of incurring the repet­itive strain injuries frequently associated with heavy liquid handling workloads.

The PIPETBOY provides users with a high level of control over liquid levels during serological pipetting, and the team uses this superior control to streamline the dispensing of cells and exchange of media between different labware formats across various aspects of their workflows. This has notice­ably enhanced the speed, accuracy, and repro­ducibility of all the lab’s complicated pipetting tasks, contributing to improving the quality of their research outcomes.

SUMMARY

The new knowledge gained from studying the role of the AhR in immune sensing and signaling dynamics will certainly play a key role in the devel­opment of novel personalized therapeutic strategies for both infectious diseases and cancers in the fu­ture, and already holds much promise for improv­ing patient outcomes through custom treatment solutions. Although still in early days, the cutting-edge AhR research being carried out by the Im­mune Sensing and Signaling Dynamics Group at i3S may prove to be a foundation for bridging the gap between fundamental immunology research and clinical applications and could ultimately help to accelerate the field of personalized medicine.

REFERENCE

1. https://www.mdpi.com/2075-1729/13/5/1099.

Dr. Pedro Moura Alves has been Group Leader of the Immune Sensing and Signaling Dynamics Group at i3S since February 2022. He studied Biochemistry at Universidade da Beira Interior, Portugal, graduating in 2004, and moved to Boston, MA in 2005 to embark upon a PhD within the group of Prof. Bruce Walker. He returned to Portugal in 2007 and joined the group of Dr. Luís Ferreira Moita, finishing his PhD in 2010, and then became a post-doctoral fellow at the Max Planck Institute for Infection Biology. In March 2019, he started his independent research group at the Ludwig Institute for Cancer Research, University of Oxford, UK.