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Open Access 01-12-2018 | Research

miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy

Authors: Qian Huang, Jiajia Xia, Lei Wang, Xu Wang, Xiaodong Ma, Qipan Deng, Yong Lu, Munish Kumar, Zhiyuan Zhou, Ling Li, Zhaoyang Zeng, Ken H. Young, Qing Yi, Mingzhi Zhang, Yong Li

Published in: Journal of Hematology & Oncology | Issue 1/2018

Abstract

Background

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting step in converting tryptophan to kynurenine. Chimeric antigen receptor (CAR) T cells are T cells with recombinant receptors targeting tumor-associated antigens. The Food and Drug Administration has approved CAR T cells that target CD19 for treatment of advanced B cell leukemia and lymphoma. However, CAR T cell therapy in solid tumors has been hampered by multiple obstacles. Preclinical and clinical studies suggest that combinatorial immune checkpoint blockade and IDO1 inhibition provide durable therapeutic efficacy against cancer. Yet, the combination of IDO1 inhibition and CAR T has not been attempted.

Methods

We analyze IDO1 downregulation by miR-153 in colon cancer cells and the association of IDO1 and miR-153 expression with colorectal patient survival. We generate CAR T cells targeting the epidermal growth factor receptor variant III and measure their tumor killing effects against colon cancer cells with or without miR-153 overexpression by killing assays and in xenografts.

Results

IDO1 is highly expressed in colorectal tumors and is inversely associated with patient survival. miR-153 directly inhibits IDO1 expression by targeting its 3′ untranslated region in colon cancer cells; yet, miR-153 overexpression does not affect cancer cell survival, apoptosis, and colony formation. When colon cancer cells are targeted by CAR T cells, miR-153 overexpression within tumor cells significantly enhances T cell killing in vitro and suppresses xenograft tumor growth in mice.

Conclusions

These findings indicate that miR-153 inhibits IDO1 expression in colon cancer cells and is a tumor-suppressive miRNA that enhances CAR T cell immunotherapy. This study supports the combinatorial use of IDO1 inhibitors and CAR T cells in treating solid tumors.

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Title: miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy
Authors: Qian Huang
Jiajia Xia
Lei Wang
Xu Wang
Xiaodong Ma
Qipan Deng
Yong Lu
Munish Kumar
Zhiyuan Zhou
Ling Li
Zhaoyang Zeng
Ken H. Young
Qing Yi
Mingzhi Zhang
Yong Li
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2018
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-018-0600-x

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