Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • Cancers that responded to immune checkpoint inhibitors were

    2024-04-02

    Cancers that responded to immune checkpoint inhibitors were shown to present a type I interferon (IFN) signature in the TME 33, 34. Type I IFNs positively regulate the expression of tumor antigens and their crosspresentation by DCs to tumoricidal CTLs. Furthermore, CD8+ T cell develops full effector functions in the presence of type I IFNs [35]. The activation of TANK-binding kinase 1 (TBK1) phosphorylates the transcription factor IRF3 (interferon regulatory transcription factor 3) that in turn upregulates gene expression of type I IFN. Further, type I IFN produced by DCs also potently induces IDO1, which serves as a cell-autonomous control of type I IFN and antagonizes its downstream effects 36, 37. AhR activation was shown to negatively regulate the type I IFN response by promoting the expression of the TCDD-inducible poly(ADP-ribose) polymerase (TiPARP). TiPARP suppresses the kinase activity of TBK1 by ADP-ribosylation, which impairs the expression of type I IFNs [38]. AhR also functions as an intracellular pattern recognition receptor, and, by detecting bacteria-derived polyaromatic pigments, controls host antibacterial responses [39]. AhR activation may therefore disturb the innate immune responses to support tumor growth. In addition to the formation of AhR agonists KYN and kynurenic acid, tryptophan is the source of several high-affinity AhR ligands. Among them, 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic 1661010 receptor methyl ester (ITE) are among the best-characterized and widely used tool molecules to delineate the immunological functions of AhR (Figure 3). The dissociation constant (Kd) of FICZ with AhR is 0.07nM [40], about five orders of magnitude lower than that of KYN (∼4μM). FICZ was first identified as a UV-mediated dimerization product of tryptophan and was found at measurable levels in skin tissue. Through the activation of AhR, FICZ is thought to contribute to the physiology and pathology of the skin 40, 41. Recent studies have also provided evidence of enzymatic pathways for the biosynthesis of FICZ, with indole-3-acetaldehyde being identified as a key intermediate [42]. ITE has a Ki of 3nM for murine AhR and was first isolated from porcine lung tissue [43]. Subsequent biochemical analyses indicated that ITE is a biochemical reaction product of tryptophan and cysteine, although details of the biochemical pathway remain to be elucidated. Using these tool molecules, it has been established that the immune responses induced by ligand-activated AhR are context- and ligand-dependent. For instance, treatment of native T lymphocytes with the high-affinity ligands TCDD and FICZ in vitro increases the cell populations of the suppressive Treg and inflammatory Th17 cells, respectively 44, 45. Activation of AhR with ITE in vitro causes significant increases in Treg cells in the spleen and blood of the treated mice [46]. However, the importance of the high-affinity AhR agonists FICZ and ITE in inducing tumor-supportive immunity requires further investigations. Although the dominant view of the immunomodulatory effects of ligand-activated AhR weighs heavily toward immunosuppression, the evidence also supports an antitumor immune response imparted by AhR activation. NK cells from murine spleen express AhR, and NK cells treated with FICZ in vitro demonstrated enhanced IFN-γ production and cytolytic activity. FICZ, through activation of AhR in NK cells, inhibited the growth of RMA-S murine lymphoma tumor cells in wild-type immunocompetent mice as well as that of B16 melanoma tumors in Rag1−/− immunocompromised mice [47]. Further, human NK cells treated with the AhR agonist FICZ together with IL-2 showed enhanced degranulation and cytotoxicity [48]. AhR was also identified as a molecular switch that controls the differentiation of myeloid cells. Ligand activation of AhR biased the differentiation of monocytes into monocyte-derived DCs over monocyte-derived macrophages [49]. Monocyte-derived DCs are major source of the proinflammatory cytokine IL-23, and induce the formation of proinflammatory Th17 cells. Conversely, monocyte-derived macrophages in the TME contribute to immunosuppression and support tumor immune escape. Therefore, the polarization toward DCs via AhR activation may activate innate antitumor immunity. Further studies will be necessary to delineate the ligand- and context-dependent AhR activation and functional responses, particularly within the arena for the development of effective immune-oncology (IO) therapies.