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

Journal of Hematology & Oncology

Zhaoyang Zeng¹  Qian Huang²  Yong Lu²  Jiajia Xia²  Xu Wang²  Qipan Deng²  Zhiyuan Zhou²  Xiaodong Ma²  Lei Wang²  Yong Li²  Munish Kumar²  Qing Yi²  Ken H. Young³  Ling Li⁴  Mingzhi Zhang⁴ 

[1] Cancer Research Institute, Central South University;Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic;Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center;Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Lymphoma Diagnosis and Treatment Center of Henan Province;

关键词: Chimeric antigen receptor (CAR);    T cells;    Indoleamine 2,3-dioxygenase 1 (IDO1);    miR-153;    Colon cancer;    Tumor microenvironment;   

DOI  :  10.1186/s13045-018-0600-x

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown