Lung Adenocarcinoma Expression of the Aryl Hydrocarbon Receptor Promotes PD-L1 and Immune Suppression

Abstract Immunotherapy has shown dramatic results in treating cancer, but only a minority of patients benefit. Therefore, there is an unmet medical need to understand the regulation of immune suppression in tumors. We show that the aryl hydrocarbon receptor (AhR) is a central player in regulating immune checkpoints in a mouse model of lung adenocarcinoma (LUAD). Within the murine malignant cell, AhR regulates expression of several genes important to suppressive immune signaling, including PD-L1. We find similar immune-related regulatory mechanisms in human LUAD cells. Notably, the presence of IFNγ boosts the expression of these AhR-regulated suppressive genes, suggesting a deleterious role for IFNγ in LUAD. Transplantation of mouse AhR-knockout CMT167 (CMT167 AhR-KO) LUAD cells leads to partial or complete tumor rejection and protection from wild type (WT) LUAD challenge. CMT167 AhR-KOtumors that do form have decreased PD-L1 expression and increased T cell infiltration relative to AhR +control tumors. To identify specific immune cell subsets involved in AhR-related tumor immunity, we employed an imaging mass cytometry (IMC) platform coupled with single cell RNA sequencing of tumor infiltrating CD45 +immune cells. Understanding the phenotypes and spatial orientation of the immune cells interacting with malignant cells will provide evidence of the key immune populations responsible for anti-tumor immunity and thus help pave the way for future therapies and biomarkers relevant to improving treatments for LUAD patients. Find the Cause Consortium Gifts