Indoleamine 2, 3-dioxygenases (IDO1 and IDO2) and tryptophan 2, 3-dioxygenase (TDO) are tryptophan catabolic enzymes that catalyze the conversion of tryptophan into kynurenine. The depletion of tryptophan and the increase in kynurenine exert important immunosuppressive functions by activating T regulatory cells and myeloid-derived suppressor cells, suppressing the functions of effector T and natural killer cells, and promoting neovascularization of solid tumors. Targeting IDO1 represents a therapeutic opportunity in cancer immunotherapy beyond checkpoint blockade or adoptive transfer of chimeric antigen receptor T cells. In this review, we discuss the function of the IDO1 pathway in tumor progression and immune surveillance. We highlight recent preclinical and clinical progress in targeting the IDO1 pathway in cancer therapeutics, including peptide vaccines, expression inhibitors, enzymatic inhibitors, and effector inhibitors.

Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are currently limited to a minority of patients and there is a need to develop a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (T_reg) cells play pivotal roles in hindering the anticancer immunity. T_reg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind to CD80 and CD86 with a higher affinity than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of the ICI response with CTLA-4 expression in T_reg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap.

Epstein-Barr virus (EBV) is reportedly the first identified human tumor virus, and is closely related to the occurrence and development of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and several lymphomas. PD-L1 expression is elevated in EBV-positive NPC and GC tissues; however, the specific mechanisms underlying the EBV-dependent promotion of PD-L1 expression to induce immune escape warrant clarification. EBV encodes 44 mature miRNAs. In this study, we find that EBV-miR-BART11 and EBV-miR-BART17-3p upregulate the expression of PD-L1 in EBV-associated NPC and GC. Furthermore, EBV-miR-BART11 targets FOXP1, EBV-miR-BART17-3p targets PBRM1, and FOXP1 and PBRM1 bind to the enhancer region of PD-L1 to inhibit its expression. Therefore, EBV-miR-BART11 and EBV-miR-BART17-3p inhibit FOXP1 and PBRM1, respectively, and enhance the transcription of PD-L1 (CD274, http://www.ncbi.nlm.nih.gov/gene/29126), resulting in the promotion of tumor immune escape, which provides insights into potential targets for EBV-related tumor immunotherapy.

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.

Atherosclerosis (AS) is chronic inflammation in response to lipid accumulation. MicroRNA-155 (miR-155) is being increasingly studied to evaluate its potential as diagnostic biomarkers and therapeutic targets in many diseases. However, delineating the role of miR-155 in AS remains difficult. Here, we detected constitutive expression of several microRNAs (miRNAs) possibly associated with cardiovascular disease in foam cells and clinical specimens from patients with AS. Among them, we found that the level of miR-155 in foam cells was the most significantly elevated in a dose- and time-dependent manner. In addition, the expression of miR-155 was elevated in the plasma and plaque of patients with AS. We also reported for the first time that miR-155 targets calcium-regulated heat stable protein 1 (CARHSP1), which regulates the stability of tumor necrosis factor alpha (TNF-α) mRNA. Furthermore, we investigated the mechanism by which the miR-155 level is elevated. miR-155 upregulation is due to transcriptional regulation by nuclear factor (NF)-κB, which is activated by the inflammatory factor TNF-α. In summary, increased miR-155 relieves chronic inflammation by a negative feedback loop and plays a protective role during atherosclerosis-associated foam cell formation by signaling through the miR-155–CARHSP1–TNF-α pathway.