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Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer

Baosheng Chen1, David M Alvarado2, Micah Iticovici2

  • 1Inflammatory Bowel Diseases Center and the Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri. mciorba@wustl.edu bchen@wustl.edu.

Cancer Immunology Research
|March 5, 2020
PubMed

Insights

Blocking indoleamine 2,3 dioxygenase 1 (IDO1) enhances colorectal cancer radiation therapy effectiveness. IDO1 inhibition sensitizes tumors to radiation-induced cell death and reduces normal tissue toxicity.

Area of Science:

  • Oncology
  • Immunology
  • Radiotherapy

Background:

  • Colorectal cancer (CRC) is a leading cause of cancer mortality globally.
  • Current treatments like chemotherapy and radiation are standard for locally advanced CRC.
  • Immune-targeting therapies benefit only a small subset of CRC patients.
  • Indoleamine 2,3 dioxygenase 1 (IDO1) expression correlates with poor CRC outcomes but remains understudied as a therapeutic target.

Purpose of the Study:

  • To investigate the interplay between the IDO1 pathway and radiotherapy in colorectal cancer.
  • To evaluate IDO1 inhibition as a strategy to enhance radiotherapy efficacy in CRC.
  • To explore the impact of IDO1 blockade on both tumor response and normal tissue toxicity.

Main Methods:

  • Utilized human and mouse CRC cell lines, organoids, and syngeneic tumor graft models.
  • Employed the clinical IDO1 inhibitor epacadostat and genetic disruption to block IDO1 activity.
  • Analyzed CRC tissues from patients who underwent radiotherapy.
  • Assessed tumor microenvironment changes, including cytokine and myeloid cell modulation.

Main Results:

  • Radiation therapy induced IDO1 overexpression in CRC via type I and II interferon signaling.
  • IDO1 enzymatic activity directly impacted CRC radiation sensitivity; inhibition sensitized cells to radiation-induced death.
  • The IDO1 metabolite kynurenine exhibited radioprotective effects.
  • IDO1 inhibition enhanced Th1 cytokines and myeloid cell-modulating factors, promoting an abscopal effect.
  • IDO1 blockade protected the small intestinal epithelium from radiation toxicity and accelerated recovery from weight loss.

Conclusions:

  • IDO1 inhibition significantly potentiates the effectiveness of radiotherapy in colorectal cancer.
  • IDO1 blockade offers a dual benefit by enhancing anti-tumor responses and mitigating radiation-induced side effects.
  • These findings provide a strong rationale for investigating IDO1 inhibitors as adjuvant therapy alongside radiation for locally advanced CRC.

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