Editorial: Targeting Indoleamine 2,3-dioxygenases and Tryptophan Dioxygenase for Cancer Immunotherapy

Brochez, Liève; Krüse, Vibeke; Schadendorf, Dirk; Muller, Alexander J.; Prendergast, George C.

doi:10.3389/fimmu.2021.789473

Cited by 2 publications

(3 citation statements)

References 11 publications

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“…Therefore, the study of these two immunosuppressive molecules is important not only for HPV-related tumor, but also for other tumor types. Considering that immunometabolism has emerged as a central element in cancer therapy ( 52 , 53 ), we previously explored the combination of gDE7 with IDO inhibitors and melatonin, which promoted synergic antitumor effects drawing attention to the relevance of multi-target therapeutic approaches ( 27 ). Focusing on continuing this study and further understanding the IDO/IL6 axis in HPV-related tumors, in the present study we investigated the outcomes of gDE7 immunization in IL-6 -/- mice, treated or not with 1MT isoforms, based on the hypothesis that targeting IDO and IL-6 could augment the immunotherapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy

Pagni

Souza²,

Pegoraro³

et al. 2022

Front. Immunol.

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High-risk Human papillomavirus (HPV) infections represent an important public health issue. Nearly all cervical malignancies are associated with HPV, and a range of other female and male cancers, such as anogenital and oropharyngeal. Aiming to treat HPV-related tumors, our group developed vaccines based on the genetic fusion of the HSV-1 glycoprotein D (gD) with the HPV-16 E7 oncoprotein (gDE7 vaccines). Despite the promising antitumor results reached by gDE7 vaccines in mice, combined therapies may increase the therapeutic effects by improving antitumor responses and halting immune suppressive mechanisms elicited by tumor cells. Considering cancer immunosuppressive mechanisms, indoleamine-2,3-dioxygenase (IDO) enzyme and interleukin-6 (IL-6) stand out in HPV-related tumors. Since IL-6 sustained the constitutive IDO expression, here we evaluated the therapeutic outcomes achieved by the combination of active immunotherapy based on a gDE7 protein-based vaccine with adjuvant treatments involving blocking IDO, either by use of IDO inhibitors or IL-6 knockout mice. C57BL/6 wild-type (WT) and transgenic IL-6-/- mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyl-tryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO. In vitro, the 1MT isoforms reduced IL-6 gene expression and IL-6 secretion in TC-1 cells. In vivo, the multi-targeted treatment improved the antitumor efficacy of the gDE7-based protein vaccine. Although the gDE7 immunization achieves partial tumor mass control in combination with D-1MT or DL-1MT in WT mice or when administered in IL-6-/- mice, the combination of gDE7 and 1MT in IL-6-/- mice further enhanced the antitumor effects, reaching total tumor rejection. The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPV-related tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy

Pagni

Souza²,

Pegoraro³

et al. 2022

Front. Immunol.

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show abstract

“…Meanwhile, these immunosuppressive cells endow iTME with the characteristics of supporting tumor progression and metastasis by secreting immunosuppressive cytokines, such as soluble proteins, enzymes, acidic and toxic metabolites (e.g., IDO, COX-2, epidermal growth factor, TGF-β, IL-10, and IL-35), and consequently inhibit the function of infiltrating APC, T cells, or other immune cells to harvest the purpose of resisting immunotherapy. To a large extent, tumor cells mediate tryptophan metabolism in T cells through overexpression of IDO and tryptophan-2, 3-dioxygenase, to convert tryptophan to kynurenine and its metabolites . Both tryptophan deficiency and kynurenine accumulation can inhibit the function of effector T cells.…”

Section: Immune Escape and Immunotherapy Classificationmentioning

confidence: 99%

“…To a large extent, tumor cells mediate tryptophan metabolism in T cells through overexpression of IDO and tryptophan-2, 3-dioxygenase, to convert tryptophan to kynurenine and its metabolites. 45 Both tryptophan deficiency and kynurenine accumulation can inhibit the function of effector T cells. In addition, the expression of immune checkpoint molecules on tumor cells and CTLA-4, T cell immunoglobulin 3, PD-L1 on TAMs, MDSCs or Tregs can also be induced and up-regulated in hypoxic iTME, so that tumor cells can escape the killing effect mediated by T cells and NK cells.…”

Section: Immune Escape and Immunotherapy Classificationmentioning

confidence: 99%

Advanced Generation Therapeutics: Biomimetic Nanodelivery System for Tumor Immunotherapy

Li,

Zeng,

et al. 2023

ACS Nano

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Editorial: Targeting Indoleamine 2,3-dioxygenases and Tryptophan Dioxygenase for Cancer Immunotherapy

Cited by 2 publications

References 11 publications

Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy

Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy

Advanced Generation Therapeutics: Biomimetic Nanodelivery System for Tumor Immunotherapy

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