Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

LAG3 is the most promising immune checkpoint next to PD-1 and CTLA-4. High LAG3 and FGL1 expression boosts tumor growth by inhibiting the immune microenvironment. This review comprises four sections presenting the structure/expression, interaction, biological effects, and clinical application of LAG3/FGL1. D1 and D2 of LAG3 and FD of FGL1 are the LAG3-FGL1 interaction domains. LAG3 accumulates on the surface of lymphocytes in various tumors, but is also found in the cytoplasm in non-small cell lung cancer (NSCLC) cells. FGL1 is found in the cytoplasm in NSCLC cells and on the surface of breast cancer cells. The LAG3-FGL1 interaction mechanism remains unclear, and the intracellular signals require elucidation. LAG3/FGL1 activity is associated with immune cell infiltration, proliferation, and secretion. Cytokine production is enhanced when LAG3/FGL1 are co-expressed with PD-1. IMP321 and relatlimab are promising monoclonal antibodies targeting LAG3 in melanoma. The clinical use of anti-FGL1 antibodies has not been reported. Finally, high FGL1 and LAG3 expression induces EGFR-TKI and gefitinib resistance, and anti-PD-1 therapy resistance, respectively. We present a comprehensive overview of the role of LAG3/FGL1 in cancer, suggesting novel anti-tumor therapy strategies.

Systematic pan-cancer landscape identifies CARM1 as a potential prognostic and immunological biomarker

Background Belonging to the protein arginine methyltransferase (PRMT) family, the enzyme encoded by coactivator associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of protein arginine residues, especially acts on histones and other chromatin related proteins, which is essential in regulating gene expression. Beyond its well-established involvement in the regulation of transcription, recent studies have revealed a novel role of CARM1 in tumorigenesis and development, but there is still a lack of systematic understanding of CARM1 in human cancers. An integrated analysis of CARM1 in pan-cancer may contribute to further explore its prognostic value and potential immunological function in tumor therapy. Results Based on systematic analysis of data in multiple databases, we firstly verified that CARM1 is highly expressed in most tumors compared with corresponding normal tissues, and is bound up with poor prognosis in some tumors. Subsequently, relevance between CARM1 expression level and tumor immune microenvironment is analyzed from the perspectives of tumor mutation burden, microsatellite instability, mismatch repair genes, methyltransferases genes, immune checkpoint genes and immune cells infiltration, indicating a potential relationship between CARM1 expression and tumor microenvironment. A gene enrichment analysis followed shortly, which implied that the role of CARM1 in tumor pathogenesis may be related to transcriptional imbalance and viral carcinogenesis. Conclusions Our first comprehensive bioinformatics analysis provides a broad molecular perspective on the role of CARM1 in various tumors, highlights its value in clinical prognosis and potential association with tumor immune microenvironment, which may furnish an immune based antitumor strategy to provide a reference for more accurate and personalized immunotherapy in the future.

Immune infiltration and a ferroptosis-related gene signature for predicting the prognosis of patients with cholangiocarcinoma

Background Cholangiocarcinoma (CHOL) is a digestive tract tumor with high malignancy and poor prognosis and is extremely challenging to treat. At present, induced cell death holds great promise in tumor therapy. Ferroptosis is a recently proposed pattern of programmed cell death, and numerous studies have shown that it is intimately involved in tumors. However, the roles of differentially expressed ferroptosis-related genes (DEFRGs) in CHOL have not been investigated. Methods Our study was based on the The Cancer Genome Atlas (TCGA) database, DEFRGs were obtained to construct a prognostic riskScore model of CHOL by univariate and multivariate Cox regression analyses. Subsequently, the model was evaluated by nomogram construction, survival analysis, receiver operating characteristic (ROC) analysis and exploration of the immune microenvironment, and the mRNA and protein expression levels of each gene in the model were validated by Gene Expression Omnibus (GEO) database and quantitative real-time PCR (qRT-PCR). Results We screened four DEFRGs from the TCGA database to construct a prognostic model. The construction of a nomogram confirmed the predictive value of the model for overall survival (OS), and it was confirmed to have high diagnostic value by ROC analysis. The GSEA results suggested that these genes were mainly enriched in ferroptosis- and metabolism-related pathways. Finally, our experimental results validated the expression levels of the four DEFRGs, which were almost consistent with our bioinformatics results. Conclusion Our study found that the prognostic model showed extremely high diagnostic and prognostic value and could predict the possibility of immunotherapy, thus providing a new direction for individualized treatment of patients with CHOL.

Identification of Novel Prognostic Risk Signature of Breast Cancer Based on Ferroptosis-Related Genes

Ferroptosis is a non-small molecule-induced form of tumor cell apoptosis, which has been shown to regulate the biological behavior of tumors. Therefore, genes controlling ferroptosis may be promising candidate biomarkers for tumor therapy. In this study, we investigate the function of genes associated with ferroptosis in breast cancer (BC) and systematically evaluate the relationship between ferroptosis-related gene expression profiles and prognosis in BC patients based on the Cancer Genome Atlas RNA-sequencing dataset (TCGA). By using the non-negative matrix factorization clustering method, 1,203 breast cancer samples were clustered into two clearly divided subgroups based on the expression of 237 ferroptosis-related genes. The least absolute shrinkage and selection operator (LASSO) was used to develop risk profiles for five genes, and then these five genes were verified by the polymerase chain reaction (PCR). The relationship between genetic risk characteristics and clinical characteristics of BC is described. The results show that the genetic risk signature associated with clinical characteristics can be used as independent prognostic indicators for BC patients.

Homologous tumor cell membrane vesicles active preferential self-recognition of tumor cells in vitro

Cell membrane vesicles, as delivery carriers of drugs or biological agents in vivo, are an important therapeutic mode in the study of disease treatment. Tumor membrane-derived vesicles have been widely used in tumor therapy because of their good tumor enrichment effect. The most common method is the surface of nanoparticles coated with tumor cell membrane, which can effectively prolong the circulation time of particles in the blood and the enrichment of tumors. In this study, we prepared vesicles of different tumor cell membrane derivate and studied their targeting to tumors detailly. The results showed that homologous vesicles have high targeting to homologous tumor cells. The fluorescence of vesicles in homologous tumor cells was significantly higher than that in other tumor cells. This study will provide a new strategy and guidance for the clinical treatment of cancer based on the tumor cell membrane system. Graphical Abstract

A “Double-Locked” and Enzyme/pH-Activated Theranostic Agent for Accurate Tumor Imaging and Therapy

Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the “double-locked” strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-β-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of β-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first “key”) and pH (second “key”), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.

Charge reversal nano-systems for tumor therapy

Surface charge of biological and medical nanocarriers has been demonstrated to play an important role in cellular uptake. Owing to the unique physicochemical properties, charge-reversal delivery strategy has rapidly developed as a promising approach for drug delivery application, especially for cancer treatment. Charge-reversal nanocarriers are neutral/negatively charged at physiological conditions while could be triggered to positively charged by specific stimuli (i.e., pH, redox, ROS, enzyme, light or temperature) to achieve the prolonged blood circulation and enhanced tumor cellular uptake, thus to potentiate the antitumor effects of delivered therapeutic agents. In this review, we comprehensively summarized the recent advances of charge-reversal nanocarriers, including: (i) the effect of surface charge on cellular uptake; (ii) charge-conversion mechanisms responding to several specific stimuli; (iii) relation between the chemical structure and charge reversal activity; and (iv) polymeric materials that are commonly applied in the charge-reversal delivery systems. Graphical Abstract