Linping Xu

The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.

mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

AIMS: Alcohol intake has been shown to increase the risk of breast cancer. However, the dose-response analysis of different alcoholic beverages (spirits, wine and beer) is not clear. Our meta-analysis aims to provide a dose-response estimation between different alcohols and breast cancer risk. METHODS: Search of PubMed and Web of Science and manual searches were conducted up to 1 December 2018, and summary relative risks (RRs) and attributable risk percentage (ARP) for alcohol intake on the development of breast cancer were calculated. Dose-response meta-analysis modeled relationships between drinking type and breast cancer risk. Sources of heterogeneity were explored, and sensitivity analyses were conducted to test the robustness of findings. RESULTS: In total, 22 cohort studies and 45,350 breast cancer cases were included. Current drinkers for ER+ had an increased risk compared with never drinkers. In dose-response analysis, there was a statistically significant linear trend with breast cancer risk increasing gradually by total alcohol and wine dose: when adding 10 g per day, the risk increased by 10.5% (RR = 1.10, 95%CI = 1.08-1.13) in total alcohol and 8.9% (RR = 1.08, 95%CI = 1.04-1.14) in wine. For postmenopausal women, the risk increases by 11.1% (RR = 1.11, 95%CI = 1.09-1.13) with every 10 g of total alcohol increase. Furthermore, the breast cancer alcohol-attributed percentage is higher in Europe than in North America and Asia. CONCLUSIONS: The effect of drinking on the incidence of breast cancer is mainly manifested in ER+ breast cancer. Quantitative analysis showed total drinking had a significant risk for breast cancer, especially for postmenopausal women. However, for different alcohols, just wine intake has the similar results.