Anti-IDO1 monoclonal antibody, clone 10.1

Cervical cancer is the fourth most common cancer in women around the world. Cancer stem cells (CSCs) are responsible for cancer initiation, as well as resistance to radiation therapy, and are considered as the effective target of cancer therapy. Indoleamine 2,3-dioxygenase 1 (IDO1) mediates tryptophan metabolism and T cell suppression, but the immune-independent function of IDO1 in cancer behavior is not fully understood. Using tumorsphere cultivation for enriched CSCs, we firstly found that IDO1 was increased in HeLa and SiHa cervical cancer cells and in these two cell lines after radiation treatment. The radiosensitivity of HeLa and SiHa tumorsphere cells was increased after the inhibition of IDO1 through RNA interference or by the treatment of INCB-024360, an IDO1 inhibitor. With the treatment of kynurenine, the first breakdown product of the IDO1-mediated tryptophan metabolism, the radiosensitivity of HeLa and SiHa cells decreased. The inhibition of Notch1 by shRNA downregulated IDO1 expression in cervical CSCs and the binding of the intracellular domain of Notch (NICD) on the IDO1 promoter was reduced by Ro-4929097, a gamma-secretase inhibitor. Moreover, the knockdown of IDO1 also decreased NICD expression in cervical CSCs, which was correlated with the reduced binding of aryl hydrocarbon receptor nuclear translocator to Notch1 promoter. In vivo treatment of INCB-0234360 sensitized SiHa xenograft tumors to radiation treatment in nude mice through increased DNA damage. Furthermore, kynurenine increased the tumorsphere formation capability and the expression of cancer stemness genes including Oct4 and Sox2. Our data provide a reciprocal regulation mechanism between IDO1 and Notch1 expression in cervical cancer cells and suggest that the IDO1 inhibitors may potentially be used as radiosensitizers.

Immunotherapeutic agents have demonstrated encouraging signs of clinical utility in non-Hodgkin lymphoma. The goal of this study is to analyze the immune characteristics of Chinese patients with diffuse large B-cell lymphoma (DLBCL) to inform the development of immunotherapies in this patient population. Tumor samples from 211 DLBCL patients were analyzed for cell of origin (COO) and immune characteristics using the NanoString platform as well as MYC protein expression through immunohistochemistry. Lower incidence of the germinal center B-cell (GCB) subtype (93/211, 44.1%) was observed in this cohort. Compared to the GCB subtype, the activated B-cell (ABC) subtype was associated with significantly increased expression of multiple pro-inflammatory gene signatures and decreased expression of anti-inflammatory gene signatures. Instead of affecting the pro-inflammatory genes, MYC protein overexpression showed a negative correlation with the expression of T-cell receptor (TCR) and T regulatory genes as well as the OX40 gene. Regardless of COO, higher PD-L1 or IDO1 gene expression correlated with increased expression of T effector and Interferon-gamma gene signatures while the expression of multiple oncogenes including ACTR3B, ERBB2, AKT2 and SMARCD1 was down-regulated. Our findings may thus be helpful in guiding further development of immunotherapies for the different subsets of Chinese DLBCL patients. (C) 2018 The Authors. Published by Elsevier B.V.