Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

Gargaro, Marco; Manni, Giorgia; Scalisi, Giulia; Puccetti, Paolo; Fallarino, Francesca

doi:10.3390/ijms22094644

Cited by 29 publications

(19 citation statements)

References 86 publications

(111 reference statements)

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“…It is well-established the activation of AhR in immune cells hinders efficient antitumor immunity via stimulation of antigen-presenting DCs, tumor-associated macrophages (TAMs), immunosuppressive Tregs and modulation of effector CD8 and CD4 T-cell functions (111). Beside hampering the modulation of Kyn, inhibition of AhR signaling activation with small-molecule antagonists is an alternative strategy, which seeks to interfere with the immunosuppression functions regardless of the origin of Kyn (112). A major challenge to the development of selective AhR modulators reside in its ligand promiscuity (113).…”

Section: Synthetic Ahr Modulatorsmentioning

confidence: 99%

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

Peyraud

Guégan²,

Bodet³

et al. 2022

Front. Immunol.

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Metabolism of tryptophan (Trp), an essential amino acid, represent a major metabolic pathway that both promotes tumor cell intrinsic malignant properties as well as restricts antitumour immunity, thus emerging as a drug development target for cancer immunotherapy. Three cytosolic enzymes, namely indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO2), catalyzes the first-rate limiting step of the degradation of Trp to kynurenine (Kyn) and modulates immunity toward immunosuppression mainly through the aryl hydrocarbon receptor (AhR) activation in numerous types of cancer. By restoring antitumor immune responses and synergizing with other immunotherapies, the encouraging preclinical data of IDO1 inhibitors has dramatically failed to translate into clinical success when combined with immune checkpoints inhibitors, reigniting the debate of combinatorial approach. In this review, we i) provide comprehensive evidences on immunomodulatory role of the Trp catabolism metabolites that highlight this pathway as relevant target in immuno-oncology, ii)ii) discuss underwhelming results from clinical trials investigating efficacy of IDO1 inhibitors and underlying mechanisms that might have contributed to this failure, and finally, iii) discuss the current state-of-art surrounding alternative approaches of innovative antitumor immunotherapies that target molecules of Trp catabolism as well as challenges and perspectives in the era of immunotherapy.

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Section: Synthetic Ahr Modulatorsmentioning

confidence: 99%

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

Peyraud

Guégan²,

Bodet³

et al. 2022

Front. Immunol.

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“…The downstream metabolite 3HAA shifts the proinflammatory and anti-inflammatory balance directly by inhibiting Th1 cell differentiation and function (58) and may also influence the expression of nuclear transcription coactivators (61). Microbial invasion and tumour aggression are therefore facilitated by the expression of IDO1 and its suppression of host immune surveillance and cell destruction (62,63), coupled with suppression of the differentiation and activity of effector T cells and NK cells (16,19,(64)(65)(66).…”

Section: Discussionmentioning

confidence: 99%

Induction of IDO1 and Kynurenine by Serine Proteases Subtilisin, Prostate Specific Antigen, CD26 and HtrA: A New Form of Immunosuppression?

et al. 2022

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Several serine proteases have been linked to autoimmune disorders and tumour initiation although the mechanisms are not fully understood. Activation of the kynurenine pathway enzyme indoleamine-2,3-dioxygenase (IDO1) modulates cellular activity in the brain, tolerogenesis in the immune system and is a major checkpoint in cancer development. We now report that IDO1 mRNA and IDO1 protein expression (generating kynurenine) are induced in human monocyte-derived macrophages by several chymotryptic serine proteases with direct links to tumorigenesis, including Prostate Specific Antigen (PSA), CD26 (Dipeptidyl-peptidase-4, CD26/DPP-4), High Temperature Requirement protein-A (HtrA), and the bacterial virulence factor subtilisin. These proteases also induce expression of the pro-inflammatory cytokine genes IL1B and IL6. Other serine proteases tested: bacterial glu-C endopeptidase and mammalian Pro-protein Convertase Subtilase-Kexin-3 (PCSK3, furin), urokinase plasminogen activator (uPA), cathepsin G or neutrophil elastase, did not induce IDO1, indicating that the reported effects are not a general property of all serine proteases. The results represent a novel mechanism of activating immunosuppressive IDO1 and inducing kynurenine generation which, together with the production of inflammatory cytokines, would contribute to tumour initiation and progression, providing a new target for drug development. In addition, the proteasomal S20 serine protease inhibitor carfilzomib, used in the treatment of myeloma, prevented the induction of IDO1 and cytokine gene expression, potentially contributing to its clinical anti-cancer activity.

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“…Whether there is a direct link between specific microbial species-mediated immune checkpoint protein expression regulation remains to be explored; however, it is known that the microbiota can regulate tryptophan processing [ 133 ]. As discussed above, the binding of tryptophan metabolites to the AHR receptor can regulate PD-1 expression.…”

Section: Impact Of Diet and The Microbiome On Immune Checkpoint Blockade Responsementioning

confidence: 99%

Metabolic Implications of Immune Checkpoint Proteins in Cancer

Stirling

Bronson

Mackert

et al. 2022

Cells

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Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

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Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

Cited by 29 publications

References 86 publications

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

Induction of IDO1 and Kynurenine by Serine Proteases Subtilisin, Prostate Specific Antigen, CD26 and HtrA: A New Form of Immunosuppression?

Metabolic Implications of Immune Checkpoint Proteins in Cancer

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