About the project
Triple negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis, which is mainly due to limited treatment options. TNBCs, like many other cancers, initiate and develop through a complex sequence of events, including metabolic reprogramming, DNA mutations and alterations in host immunity.
Immunotherapy, a type of cancer therapy that targets the immune system, has recently shown unprecedented clinical outcomes. One of the most studied types of treatments is inhibition of the immune checkpoint proteins, programmed death receptor 1 (PD1) and its ligand, PDL1. When engaged, the PD1/PDL1 axis deactivates cancer killing T cells. Immune checkpoint inhibition has resulted in impressive clinical successes across multiple solid tumors.
However, not all patients respond and 1/3 of those that do, experience relapse. Thus, new therapies are urgently needed. The aryl hydrocarbon receptor (AHR) is a transcription factor best known as a mediator of the toxic responses of environmental pollutants. Because of this, its potential as a therapeutic target has been overlooked.
AHR is now recognized as an essential gatekeeper integrating metabolic signals to promote immunosuppression, regulate effector immune cells and enhance tumorigenesis. AHR drives pro-survival processes that increase tumor growth, while its immunosuppressive actions allow tumor cells to “hide” from immunosurveillance. This application will establish the suitability of inhibiting AHR alone or in combination with immune checkpoint inhibitors to improve TNBC therapy.
Objectives
We hypothesize that loss or pharmacological inhibition of AHR, alone or in combination with immune checkpoint inhibition, reduces breast cancer growth and progression.
- Determine how loss or inhibition of AHR influences TNBC growth and migration.
- Characterize how loss or inhibition of AHR affects the interplay between TNBC and tumor associated immune cells.
- Determine how loss or inhibition of AHR alone or in combination with immune checkpoint inhibition affects tumor growth in syngeneic breast cancer models.
AHR is a driver of proliferation and cancer. It is also immunosuppressive, and its actions allow tumors to escape immunosurveillance. Our project combines cell biology, gene editing, genomics, epigenomics, unique genetically modified mouse models, and in vivo cancer models to assess AHR inhibition alone or in combination with immune checkpoint inhibition as an innovative approach in the fight against TNBC.
Background
Cancers, including breast cancers, develop through a complex set of events, including DNA mutations, changes in the expression of important regulatory proteins, and changes in the way the immune system fights cancer. It is well recognized that our immune system plays an important role in protecting us from cancer by recognizing and selectively destroying malignant cells. However, during cancer progression tumours develop a variety of ways to block the protective actions of the immune system.
Therapeutically targeting the immune system by increasing the ability of immune cells to recognize and kill tumour cells, in an approach known as immunotherapy, has led to unprecedented clinical benefit for many patients. Unfortunately, not all patients respond, and many that do, experience relapse. Therefore, there is a need to identify new therapeutic targets and alternative approaches to improve this type of anti-cancer treatment.
The aryl hydrocarbon receptor is a protein that was initially identified as the regulator of the toxicity of many environmental contaminants, including several persistent environmental pollutants such as dioxin. New research, however, has revealed that the aryl hydrocarbon receptor acts as an important regulator of dietary, environmental, and endogenous signals to modulate immune cell function and inflammation. In general, the aryl hydrocarbon receptor functions to dampen inflammation and prevent the overactivation of the immune system. In the gut, the aryl hydrocarbon receptor functions to maintain a healthy intestinal environment by reducing inflammation. This has led to significant interest in increasing aryl hydrocarbon receptor activity to treat inflammatory bowel disease.
Although, the ability of the aryl hydrocarbon receptor to reduce inflammation might be beneficial for intestinal health, in the context of cancer the actions of the aryl hydrocarbon receptor allow tumour cells to “hide” from the immune system giving them the opportunity to grow and proliferate. Thus, inhibiting aryl hydrocarbon receptor activity would increase the ability of immune cells to recognize and kill tumour cells and prevent tumour growth and progression. In this research project that was recently funded by the Norwegian research council, we will determine if inhibition of AHR, alone or in combination with current immunotherapy treatments, reduces breast cancer growth and progression.
Our studies could lead to new therapeutic options for breast cancer patients and perhaps other patients suffering from other forms of cancer.
Financing
- Norwegian Research Council
Cooperation
- Professor Akinori Takaoka, MD, PhD University of Hokkaido, Institute for Genetic Medicine, Research Section of Molecular Pathogenesis, Sapporo, Japan
- Professor Tim Zacharewski, PhD, Michigan State University, Dep. Of Biochemistry, East Lansing Michigan USA
- Assistant Professor Chiara Gorrini, University of Leeds, Leeds, UK
- Professor Bjørn Skålhegg, University of Oslo, Dep. Of Nutrition