Cell-intrinsic view of the aryl hydrocarbon receptor in tumor immunity

The aryl hydrocarbon receptor (Ahr) is a cell type-specific regulatory factor that can have both pro- and antitumor roles depending on the context and immune cell subset. Owing to the relatively wide expression pattern of Ahr in mice and humans, the effects of systemic treatment with Ahr ligands or antagonists in cancer can be potentially confounding, thus necessitating careful interpretation of experimental results. The cell-intrinsic impact of Ahr on immune versus cancer cells in tumors requires further investigation to allow the rational development of effective therapeutics. An exciting link between cancer and the microbiota has been described: some bacteria can effectively support antitumor immunity, and some of these can produce ligands that activate Ahr. Emerging insights into aryl hydrocarbon receptor (Ahr) biology have revealed its key role in regulating mammalian host immunity and tissue homeostasis. Depending on the context, immune cells can play either a pro- or antitumor role in cancer. Ahr has classically been viewed as protumorigenic; however, given recent advances in our understanding of Ahr functions, especially in the immune system, this view requires reassessment. Moreover, given its cell type-specific activity, therapeutic exploitation of the Ahr pathway should be cautiously considered. We describe the function of Ahr in different immune cells, and connect with their roles in cancer immunology. In addition, we discuss clinical perspectives of how recent advances in our understanding of Ahr biology might be therapeutically applied to improve cancer outcomes. Emerging insights into aryl hydrocarbon receptor (Ahr) biology have revealed its key role in regulating mammalian host immunity and tissue homeostasis. Depending on the context, immune cells can play either a pro- or antitumor role in cancer. Ahr has classically been viewed as protumorigenic; however, given recent advances in our understanding of Ahr functions, especially in the immune system, this view requires reassessment. Moreover, given its cell type-specific activity, therapeutic exploitation of the Ahr pathway should be cautiously considered. We describe the function of Ahr in different immune cells, and connect with their roles in cancer immunology. In addition, we discuss clinical perspectives of how recent advances in our understanding of Ahr biology might be therapeutically applied to improve cancer outcomes. animals receive a (sub)lethal dose of irradiation and are then reconstituted with exogenous bone marrow. Bone marrow chimeras help to determine the hematopoietic cell versus non-hematopoietic cell contributions of genes of interest, and can also allow more detailed investigation of the cell-intrinsic and -extrinsic roles of individual genes. a specific type of colorectal cancer caused in part by chronic inflammation of the colon. lymphocytes that can directly kill virus-infected and transformed cells via the production of various cytotoxic molecules in an antigen-specific manner (CD3+TCRβ+CD8+). these are referred to as 'professional antigen-presenting cells (APCs)' because of their superior ability to prime the adaptive immune response (CD11c+MHCII+). the collection of biochemical mechanisms that cells have evolved to combat threats posed by DNA damage. imbalance or reduction in the diversity of the microbiome; often includes loss of beneficial bacteria. a type of drug that blocks checkpoint proteins (CTLA-4, PD-1, PD-L1, etc.) expressed by immune cells or cancer cells, and which normally prevent excessive inflammation in autoimmunity but can also inhibit T cell killing of cancer cells. a cellular enzyme that converts the essential amino acid tryptophan (Trp) into the Ahr ligand kynurenine (Kyn). a distinct family of innate immune cells that play key roles in immunity, inflammation, and tissue homeostasis. Helper ILCs are categorized into at least three main subsets. ILC1s (Lin−Tbet+Eomes−) aid the cell-mediated immune response to intracellular pathogens, ILC2s (Lin−Gata3+) contribute to humoral immune response to helminth infections, and ILC3s (Lin−RORγt+) help in the response to extracellular pathogens. a lymphocyte coinhibitory receptor expressed mainly by late or terminally differentiated effector and effector memory CD8+ T and NK cells. a heterogeneous population of immature myeloid cells that are expanded and function to suppress the immune response during inflammatory conditions, infection, trauma, and cancer. cytotoxic innate immune cells that kill virus-infected and transformed cells in a nonspecific manner (mouse, CD3−Tbet+Eomes+NK1.1+ and/or NKp46+, human, CD3−NKp46+CD56bright/dim). a suppressive subset of helper T cells that prevent autoimmunity but also inhibit the antitumor immune response (CD4+TCRβ+ Foxp3+). express the nuclear hormone receptor RORγt, a key transcriptional regulator of Th17 cells and ILC3s. RORγt+ Tregs are abundantly present in the gut and require the microbiota for their generation. molecular processes underlying the properties of stem cells (i.e., self-renewal and the ability to give rise to differentiated cells). a state of T cell dysfunction that arises during chronic infections or cancer. Hallmarks include poor effector function, sustained expression of inhibitory receptors, and a transcriptional and epigenetic state distinct from that of effector and memory T cells. ectopic lymphoid organs that develop in non-lymphoid tissues at the sites of chronic inflammation including tumors. the prototypical xenobiotic ligand for Ahr and toxin that is known to cause developmental defects and cancer. a cancer genomics program that has molecularly characterized over 20 000 primary human cancer and matched normal samples spanning 33 cancer types; the data generated are publicly available for researchers to download and analyze. CTLs that remain in the tissue and constantly survey re-exposure to the same pathogen (CD69+CD103+, although the expression of these markers can vary depending on the tissue). another Trp-catabolizing enzyme that functions similarly to IDO1 to generate Kyn. the enzyme responsible for tryptophan conversion to the Ahr ligand 5-hydroxyltrptophan (5-HTP). a subpopulation of tumor cells that display stem cell-like properties and may serve as a treatment-resistant reservoir of cancerous cells that contribute to tumor regrowth. particularly adept antigen-presenting cells that are important orchestrators of antitumor immunity (CD11c+MHCII+CD103+). type 1 lymphocytes marked by their expression of Tbx21 (T-bet) and Ifng; can respond to intracellular pathogens or cancer. helper T cell subsets that function to maintain the intestinal epithelial barrier, contribute to pathogen clearance at mucosal barrier sites, and are involved in the pathogenesis of some autoimmune diseases: Th17 (CD4+TCRβ+ IL-17+) and Th22 (CD4+TCRβ+ IL-22+).