J Breast Cancer.  2019 Jun;22(2):196-209. 10.4048/jbc.2019.22.e23.

Inhibition of Indoleamine 2,3-Dioxygenase Enhances the Therapeutic Efficacy of Immunogenic Chemotherapeutics in Breast Cancer

Affiliations
  • 1Department of Clinical Medicine, Clinical Medical College of Shandong University, Jinan, China.
  • 2Department of General Surgery, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 3Department of Hepatic Surgery, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. wdjia2018@sina.com

Abstract

PURPOSE
Breast cancer has become a major public health threat in the current society. Anthracycline doxorubicin (DOX) is a widely used drug in breast cancer chemotherapy. We aimed to investigate the immunogenic death of breast tumor cells caused by DOX, and detect the effects of combination of DOX and a small molecule inhibitor in tumor engrafted mouse model.
METHODS
We used 4T1 breast cancer cells to examine the anthracycline DOX-mediated immunogenic death of breast tumor cells by assessing the calreticulin exposure and adenosine triphosphate and high mobility group box 1 release. Using 4T1 tumor cell-engrafted mouse model, we also detected the expression of indoleamine 2,3-dioxygenase (IDO) in tumor tissues after DOX treatment and further explored whether the specific small molecule IDO1 inhibitor NLG919 combined with DOX, can exhibit better therapeutic effects on breast cancer.
RESULTS
DOX induced immunogenic cell death of murine breast cancer cells 4T1 as well as the upregulation of IDO1. We also found that treatment with NLG919 enhanced kynurenine inhibition in a dose-dependent manner. IDO1 inhibition reversed CD8+ T cell suppression mediated by IDO-expressing 4T1 murine breast cancer cells. Compared to the single agent or control, combination of DOX and NLG919 significantly inhibited the tumor growth, indicating that the 2 drugs exhibit synergistic effect. The combination therapy also increased the expression of transforming growth factor-β, while lowering the expressions of interleukin-12p70 and interferon-γ.
CONCLUSION
Compared to single agent therapy, combination of NLG919 with DOX demonstrated better therapeutic effects in 4T1 murine breast tumor model. IDO inhibition by NLG919 enhanced the therapeutic efficacy of DOX in breast cancer, achieving synergistic effect.

Keyword

Breast neoplasms; Chemotherapy; Doxorubicin; Indoleamine 2,3-dioxygenase

MeSH Terms

Adenosine Triphosphate
Animals
Breast Neoplasms*
Breast*
Calreticulin
Cell Death
Doxorubicin
Drug Therapy
Indoleamine-Pyrrole 2,3,-Dioxygenase*
Kynurenine
Mice
Public Health
Therapeutic Uses
Up-Regulation
Adenosine Triphosphate
Calreticulin
Doxorubicin
Indoleamine-Pyrrole 2,3,-Dioxygenase
Kynurenine
Therapeutic Uses
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