Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Sep 2:13:953115.
doi: 10.3389/fimmu.2022.953115. eCollection 2022.

Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer

Anna Passarelli  1 , Carmela Pisano  1 , Sabrina Chiara Cecere  1 , Marilena Di Napoli  1 , Sabrina Rossetti  1 , Rosa Tambaro  1 , Jole Ventriglia  1 , Federica Gherardi  2 , Eva Iannacone  2 , Sergio Setola Venanzio  3 , Francesco Fiore  4 , Michele Bartoletti  5 , Giosuè Scognamiglio  6 , Daniela Califano  7 , Sandro Pignata  1
Affiliations
Review

Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer

Anna Passarelli et al. Front Immunol. .

Abstract

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called "kynurenine (Kyn) pathway", which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

Keywords: 3-dioxygenase (IDO); endometrial cancer; immune metabolism; immune suppression; immunotherapy; indolamine 2; kynurenine; tryptophan.

PubMed Disclaimer

Conflict of interest statement

SP received honoraria from MSD, Pfizer, AZ, Roche, Clovis, and GSK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The tumor microenvironment in endometrial cancer. Two different mechanisms of immune resistance mediated by the IDO1 enzyme activity and expression in the TME in endometrial cancer. (Left) IDO1 is constitutively expressed in cancer cells (intrinsic or primary resistance) typically in non-inflamed tumors, such as endometrial and ovarian cancers. This expression prevents the accumulation of the activated antitumor CD8+ T cells, thus inducing an immunosuppressive TME. (Right) IDO1 is induced in endometrial cells (IDO + EC cells) and other cell types (stromal and endothelial cells) by IFN-γ released by neighboring activated T or NK cells in the context of a negative feedback loop (adaptive or acquired resistance). EC, endometrial cancer; IDO1, indolamine 2,3-dioxygenase 1; PD-L1, programmed death-ligand 1; TCR, T-cell receptor; TME, tumor microenvironment.
Figure 2
Figure 2
Targeting the IDO pathway. (A) The schematic representation of the effect of IDO1 on immune system cells of TME. IDO1 inhibits immune responses through several mechanisms, including the depletion of the essential amino acid tryptophan and the overproduction of kynurenine. The tryptophan depletion can inhibit T-cell proliferation arresting the cell progression cycle. In addition to the depletion of tryptophan, the accumulation of kynurenine exerts also immunosuppressive effects through the promotion of the differentiation of FOXP3+ Tregs, the decrease in the immunogenicity of DCs, and the inhibition of T effector cell. Thus, IDO1 represents a driver of tumor-mediated suppression. (B) The IDO1 pathway inhibition directly acts on the modulation of both innate and adaptive immune system in TME. Thus, the IDO1 inhibition can potentially turn these “cold” tumors into “hot” tumors. Abbreviations: IDO1, indolamine 2,3-dioxygenase 1; MHC, major histocompatibility complex; MDSC, myeloid-derived suppressor cells; TCR, T-cell receptor; Tregs, regulatory T cells.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2021) 71:209–49. doi: 10.3322/caac.21660 - DOI - PubMed
    1. Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al. . ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer (2021) 31:12–39. doi: 10.1136/ijgc-2020-002230 - DOI - PubMed
    1. Cancer Genome Atlas Research Network. Kandoth C, Schultz N, AD C, Akbani R, Liu Y, et al. . Integrated genomic characterization of endometrial carcinoma. Nature (2013) 497:67–73. doi: 10.1038/nature12113 - DOI - PMC - PubMed
    1. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. . PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature (2014) 515:568–71. doi: 10.1038/nature13954 - DOI - PMC - PubMed
    1. Green AK, Feinberg J, Makker V. A review of immune checkpoint blockade therapy in endometrial cancer. Am Soc Clin Oncol Educ Book (2020) 40:1–7. doi: 10.1200/EDBK_280503 - DOI - PubMed

Publication types