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Indoleamine 2,3-dioxygenase in endometrial cancer: a targetable mechanism of immune resistance in mismatch repair-deficient and intact endometrial carcinomas

Modern Pathologyvolume 31pages12821290 (2018) | Download Citation

Abstract

Mismatch repair-deficient endometrial carcinomas are optimal candidates for immunotherapy given their high neoantigen loads, robust lymphoid infiltrates, and frequent PD-L1 expression. However, co-opting the PD-1/PD-L1 pathway is just one mechanism that tumors can utilize to evade host immunity. Another immune modulatory molecule that has been demonstrated in endometrial carcinoma is indoleamine 2,3-dioxygenase (IDO). We herein evaluate IDO expression in 60 endometrial carcinomas and assess results in relation to PD-L1 and mismatch repair status. IDO immunohistochemistry was performed on 60 endometrial carcinomas (20 Lynch syndrome (LS)-associated, 20 MLH1 promoter hypermethylated, and 20 mismatch repair-intact). Eight-five percent of endometrial carcinomas showed IDO tumor staining in >1% of cells. Twenty-five percent were positive in >25% of tumor cells and only 7% exceeded 50% staining. Mismatch repair-deficient cancers were more likely than mismatch repair-intact cancers to be >25% IDO-positive (35% vs. 5% p = 0.024). Differences were amplified when Lynch syndrome-associated cases were evaluated in isolation (50% Lynch syndrome-associated vs. 10% mismatch repair-intact and MLH1-hypermethylated, p = 0.001). Of the four cases showing >50% staining, three were Lynch syndrome-associated and one was MLH1-hypermethylated; no mismatch repair-intact cases had >50% staining. Forty-three percent of IDO-positive tumors were also positive for PD-L1, whereas only two cases showed tumoral PD-L1 in the absence of IDO. In summary, IDO expression is prevalent in endometrial carcinomas and diffuse staining is significantly more common in mismatch repair-deficient cancers, particularly Lynch syndrome-associated cases. Given that the majority of PD-L1 positive cancers also express IDO, synergistic combination therapy with anti-IDO and anti-PD1/PD-L1 may be relevant in this tumor type. Furthermore, anti-IDO therapy may be an option for a small subset of mismatch repair-intact cancers.

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Acknowledgements

We thank the University of Virginia Biorepository and Tissue Research Facility for their skill and expertise in performing all immunohistochemical stains.

Author information

Affiliations

  1. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    • Anne Mills
    • , Sara Zadeh
    • , Emily Sloan
    • , Zachary Chinn
    • , Susan C. Modesitt
    •  & Kari L. Ring
  2. Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of Virginia, Charlottesville, VA, USA

    • Anne Mills
    • , Sara Zadeh
    • , Emily Sloan
    • , Zachary Chinn
    • , Susan C. Modesitt
    •  & Kari L. Ring

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Anne Mills.

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DOI

https://doi.org/10.1038/s41379-018-0039-1