Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach. Nonetheless, the expression and activation of AhR can inhibit the proliferation, migration, and survival of cancer cells, and many clinically approved drugs transcriptionally activate AhR. Identification of novel select modulators of AhR-regulated transcription that promote tumor suppression is an active area of investigation. The development of AhR-targeted anticancer agents requires a thorough understanding of the molecular mechanisms driving tumor suppression. Here, we summarized the tumor-suppressive mechanisms regulated by AhR with an emphasis on the endogenous functions of the receptor in opposing carcinogenesis. In multiple different cancer models, the deletion of AhR promotes increased tumorigenesis, but a precise understanding of the molecular cues and the genetic targets of AhR involved in this process is lacking. The intent of this review was to synthesize the evidence supporting AhR-dependent tumor suppression and distill insights for development of AhR-targeted cancer therapeutics.

Thymol targeting interleukin 4 induced 1 expression reshapes the immune microenvironment to sensitize the immunotherapy in lung adenocarcinoma

“…However, out of these inhibitors, only three, namely, IK‐175, BAY2416964, and SR‐1, are in clinical trials for the treatment of cancers and for expanding hematopoietic stem cells currently. 12 The complex regulatory roles of AHR in normal physiological processes have led researchers to consider the Trp catabolic enzymes as more attractive targets for cancer therapy, rather than directly targeting AHR. Indoleamine 2,3‐dioxygenase 1 (IDO1), IDO2, and tryptophan 2,3‐dioxygenase are the main Trp catabolic enzymes.…”

Microbiome bacterial influencers of host immunity and response to immunotherapy

“…In addition, the activation of the AhR by different molecular compounds can lead to contrasting consequences, including both tumor-suppressing and tumor-promoting. 111 These observations indicate that the involvement of AhR activation in tumor immunity is dependent on the particular ligands. 110 , 111 Therefore, these results emphasize the significance of investigating the communication between bacterial ligands and AhR in tumor tissues.…”

“… 111 These observations indicate that the involvement of AhR activation in tumor immunity is dependent on the particular ligands. 110 , 111 Therefore, these results emphasize the significance of investigating the communication between bacterial ligands and AhR in tumor tissues. Elucidating effects of microbiota-derived ligands on AhR activation within CD8 + T cells will not only improve our understanding of the complex relationship between the gut microbiota and the immune system, but it may also help identify novel therapeutic targets for enhancing anti-tumor immunity and improving cancer treatment outcomes.…”

“…This activation leads to an increase in the production of IFN-γ and Granzyme B. 111 This study proposes a hypothesis that the gut microbiota, beyond its known indirect effects on immune responses and effectiveness of immunotherapy, can directly impact tumor immunity and responses to ICI therapies by translocating into the tumor microenvironment. In addition, the activation of the AhR by different molecular compounds can lead to contrasting consequences, including both tumor-suppressing and tumor-promoting.…”

“… 103 Bacteroidetes B. ovatus B. dorei B. massiliensis Anti-PD-1 Anti-PDL-1 Anti-CTLA-4 Combined therapy Melanoma, GI cancers, NSCLC, and HCC Negative Increased peripheral Tregs and MDSCs/Diminished peripheral cytokine responses Shorter PFS, Lower response rates to ICI therapy Baruch et al., 53 Gong et al., 60 Kim et al., 65 Fukuoka et al., 78 Lee et al., 108 Bender et al., 110 Elson et al. 111 Bacteroidetes B. caccae B. fragilis B. Thetaiotaomicron B. salyersiae Anti-PD-1 Anti-CTLA-4 Combined therapy Melanoma, and RCC Positive Enhanced the presence of T cell infiltrations within tumors and the frequencies of peripheral T cells Extended PFS Hayase et al., 64 Panda et al., 112 Louis et al. 113 Akkermansiaceae Anti-PD-1 Anti-PDL-1 Melanoma, NSCLC, HCC, and RCC Positive Triggering dendritic cells to release immune responses associated with Th-1 activation, resulting in the production of IL-12 and IFN-ɣ Prolonged OS durations Sivan et al., 48 Davar et al., 52 Cremonesi et al., 79 Li et al., 118 Derosa et al.…”