The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation

Abstract

Immune checkpoint inhibitors represent some of the most important cancer treatments developed in the last 20 y. However, existing immunotherapy approaches benefit only a minority of patients. Here, we provide evidence that the aryl hydrocarbon receptor (AhR) is a central player in the regulation of multiple immune checkpoints in oral squamous cell carcinoma (OSCC). Orthotopic transplant of mouse OSCC cells from which the AhR has been deleted (MOC1AhR-KO) results, within 1 wk, in the growth of small tumors that are then completely rejected within 2 wk, concomitant with an increase in activated T cells in tumor-draining lymph nodes (tdLNs) and T cell signaling within the tumor. By 2 wk, AhR+ control cells (MOC1Cas9), but not MOC1AhR-KO cells up-regulate exhaustion pathways in the tumor-infiltrating T cells and expression of checkpoint molecules on CD4+ T cells (PD-1, CTLA4, Lag3, and CD39) and macrophages, dendritic cells, and Ly6G+ myeloid cells (PD-L1 and CD39) in tdLNs. Notably, MOC1AhR-KO cell transplant renders mice 100% immune to later challenge with wild-type tumors. Analysis of altered signaling pathways within MOC1AhR-KO cells shows that the AhR controls baseline and IFNγ-induced Ido and PD-L1 expression, the latter of which occurs through direct transcriptional control. These observations 1) confirm the importance of malignant cell AhR in suppression of tumor immunity, 2) demonstrate the involvement of the AhR in IFNγ control of PD-L1 and IDO expression in the cancer context, and 3) suggest that the AhR is a viable target for modulation of multiple immune checkpoints.

The Aryl Hydrocarbon Receptor in the Pathogenesis of Environmentally-Induced Squamous Cell Carcinomas of the Skin

“…In fact, the derived tryptophan metabolites may activate AHR to generate regulatory DC which foster the expansion of Tregs while inhibiting T cell polarization towards Th17 cells (114). Noteworthy, kynurenine was found to induce the generation of immunosuppressive Tregs in mice and certain tumor entities in patients in an AHR-dependent manner (136,(138)(139)(140)(141). Along the same line, activation of AHR by its prototypic ligand TCDD promotes the expansion of CD4 + CD25 + and FoxP3 + Tregs to suppress experimental autoimmune disease (encephalomyelitis, uveoretinitis) (99,142,143).…”

“…Nevertheless, it is tempting to speculate that the UV radiation-induced formation of NFK in the skin and its further catabolism to kynurenic acid and other AHR-agonistic metabolites may, at least partially, contribute to the expansion of Tregs and the suppression of appropriate anti-tumor immune responses. As indicated by studies on patients with lung cancer or oral SCC, the activated AHR may not only enhance the expression of IDO but also attenuate the response to immune checkpoint inhibition by inducing PD-L1 ( 141 , 149 ). In addition, tumor repopulating melanoma cells may produce kynurenine and associated AHR ligands to activate AHR and induce the expression of the PD-L1 receptor PD-1 in CD8 + T cells ( 150 ).…”

Aryl hydrocarbon receptor/nuclear factor E2‐related factor 2 (AHR/NRF2) signalling: A novel therapeutic target for atopic dermatitis

“…111,112 It is unknown if tapinarof carries a similar risk. A phase 3 RCT of tapinarof 1% vs. vehicle placebo once daily is…”

AHR agonist ITE boosted PD1 antibody’s effects by inhibiting myeloid-derived cells suppressive cells in an orthotopic mouse glioma model

“…ITE could regulate one or more steps in this process. It’s known that TCDD leads to massive mobilization of MDSC with immunosuppressive activity through the regulation of CXCR2 and miR-150-5p and miR-543-3p [44] . ITE could also regulate MDSCs’ functions, as AHR expressing oral squamous carcinoma cells induced expression of checkpoint molecules PDL1 and CD39 in MDSC [45] .…”