Junshang Ge

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

Abstract Epstein–Barr virus (EBV) infection is an established cause of nasopharyngeal carcinoma (NPC) and is involved in a variety of malignant phenotypes, including tumor immune escape. EBV can encode a variety of circular RNAs (circRNA), however, little is known regarding the biological functions of these circRNAs in NPC. In this study, EBV-encoded circBART2.2 was found to be highly expressed in NPC where it upregulated PD-L1 expression and inhibited T-cell function in vitro and in vivo. circBART2.2 promoted transcription of PD-L1 by binding the helicase domain of RIG-I and activating transcription factors IRF3 and NF-κB, resulting in tumor immune escape. These results elucidate the biological function of circBART2.2, explain a novel mechanism of immune escape caused by EBV infection, and provide a new immunotherapy target for treating NPC. Significance: This work demonstrates that circBART2.2 binding to RIG-I is essential for the regulation of PD-L1 and subsequent immune escape in nasopharyngeal carcinoma.

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.

Objective: To investigate the correlation between the BRAF V600E gene mutation and clinicopathological features and thyroid function after iodine-131 treatment in patients with papillary thyroid cancer (PTC). Methods: A total of 128 PTC patients who underwent iodine-131 treatment after a total thyroidectomy from February 2015 to November 2016 at Hunan Cancer Hospital, China, were recruited. There were 25 males and 103 females. The age range was 11 to 73 years old. The BRAF V600E mutation in tumor tissues was detected by amplification-restriction mutation system polymerase chain reaction (ARMS-PCR), and the serum levels of Tg, TSH, Tg-Ab, and Tpo-Ab were measured by chemiluminescence after iodine-131 treatment. The BRAF V600E mutation was shown to be associated with clinicopathological characteristics and thyroid function indicators after iodine-131 treatment. Results: BRAF V600E mutation was detected in 75 of the 128 patients (58.6%) and was observed more frequently in cases with elevated Tg levels (Tg>1.00) at 3, 6, 12, and 18 months after treatment compared with patients without any BRAF mutations (P<0.05). Patients with BRAF V600E mutation had significant lower level of Tg-Ab at 3 and 12 months after treatment with iodine-131 than patients without BRAF V600E mutation (P<0.05). Among the 75 BRAF V600E patients, no significant association was found between the levels of TSH and Tpo-Ab after iodine-131 treatment (P>0.05). The BRAF V600E mutation was closely associated with the high-risk and age of the patient (45 years old) (P<0.05), but there was no significant correlation with gender, clinical stage, and distant metastasis.