At the intersection between autoimmune disease and cancer lies a disruption in the balance of our body’s critically important immune system, and, specifically, in its regulation. While autoimmune diseases are the result of overactivation and a failure to regulate improper responses to the body’s own tissues, cancer is the result of improper suppression and a failure to recognize and eradicate transformed malignant cells. Although they are fundamentally different conditions, overlap can be found in the pathways which are critical to disease progression and which may represent important therapeutic targets. One such pathway implicated in both autoimmunity and cancer is the aryl hydrocarbon receptor (AhR).
AhR activation suppresses immune cell activation through the modulation of T cell differentiation and antigen presenting cell (APC) function. AhR activation shows a beneficial therapeutic effect in models of autoimmune disease, but has also been implicated in driving cancer progression and tumor-mediated immunosuppression. While it is clear that the AhR plays an important role in the immune response, the mechanisms behind AhR regulation of the immune system and the effects of its modulation in autoimmunity and cancer are still not fully understood. Thus, in this work, we investigated the effect of targeting the AhR in models of autoimmunity and cancer, using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) and the murine oral cancer (MOC) model of oral squamous cell carcinoma (OSCC).
We demonstrated that AhR activation using the endogenous ligand 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induced a tolerogenic transcriptional response in mouse and human dendritic cells (DCs) associated with the induction of immunoregulatory/immunosuppressive mechanisms. We further showed that targeting the AhR using a nanoliposome (NLP) delivery platform, which co-encapsulated a MS autoantigen, suppressed the development of EAE in multiple models, both in preventative and therapeutic contexts. This disease suppression was associated with the expansion of antigen-specific FoxP3+ regulatory T cells (Treg cells) and IL10+ type 1 regulatory T cells (Tr1 cells), and a reduction in CNS-infiltrating effector T cells (Teff cells).
Using the MOC1 model of OSCC we demonstrated that deletion of the AhR in MOC1 malignant cells completely blocks in vivo tumor growth in an immune system-dependent manner and renders mice completely immune to either local or systemic re-challenge with wildtype MOC1 cells. Suppression of tumor growth was associated with a decrease in the expression of suppressive immune checkpoint markers including PD-L1 and CD39 on macrophages, dendritic cells, and Ly6G+ myeloid cells, and PD-1, CTLA4, Lag3, and CD39 on CD4+ T cells. Further, the AhR was found to control expression of chemokines and immunosuppressive IDO and PD-L1 in malignant cells themselves, suggesting that AhR activity in tumor cells may simultaneously regulate multiple immune checkpoints. Taken together, these results provide new insight into the critical role for the AhR in both autoimmunity and cancer, and confirm it as a valid therapeutic target for both diseases. / 2022-03-05T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/42228 |
| Date | 06 March 2021 |
| Creators | Kenison-White, Jessica E. |
| Contributors | Sherr, David H. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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