Immune-based combination therapy to convert immunologically cold tumors into hot tumors: an update and new insights.

As a breakthrough strategy for cancer treatment, immunotherapy mainly consists of immune checkpoint inhibitors (ICIs) and other immunomodulatory drugs that provide a durable protective antitumor response by stimulating the immune system to fight cancer. However, due to the low response rate and unique toxicity profiles of immunotherapy, the strategies of combining immunotherapy with other therapies have attracted enormous attention. These combinations are designed to exert potent antitumor effects by regulating different processes in the cancer-immunity cycle. To date, immune-based combination therapy has achieved encouraging results in numerous clinical trials and has received Food and Drug Administration (FDA) approval for certain cancers with more studies underway. This review summarizes the emerging strategies of immune-based combination therapy, including combinations with another immunotherapeutic strategy, radiotherapy, chemotherapy, anti-angiogenic therapy, targeted therapy, bacterial therapy, and stroma-targeted therapy. Here, we highlight the rationale of immune-based combination therapy, the biomarkers and the clinical progress for these immune-based combination therapies.

Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer.

BACKGROUND: The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. METHODS: Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. RESULTS: Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. CONCLUSION: TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC.

Shp2 in myocytes is essential for cardiovascular and neointima development.

Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase Shp2, cause Noonan syndrome and LEOPARD syndrome, inherited multifaceted diseases including cardiac and vascular defects. However, the function of Shp2 in blood vessels, especially in vascular smooth muscle cells (VSMCs), remains largely unknown. We generated mice in which Shp2 was specifically deleted in VSMCs and embryonic cardiomyocytes using the SM22α-Cre transgenic mouse line. Conditional Shp2 knockout resulted in massive hemorrhage, cardiovascular defects and embryonic lethality at the late embryonic developmental stage (embryonic date 16.5). The thinning of artery walls in Shp2-knockout embryos was due to decreased VSMC number and reduced extracellular matrix deposition. Myocyte proliferation was decreased in Shp2-knockout arteries and hearts. Importantly, cardiomyocyte-specific Shp2-knockout did not cause similar vascular defects. Shp2 was required for TGFß1-induced expression of ECM components, including collagens in VSMCs. In addition, collagens were sufficient to promote Shp2-inefficient VSMC proliferation. Finally, Shp2 was deleted in adult mouse VSMCs by using SMMHC-CreERT2 and tamoxifen induction. Shp2 deletion dramatically inhibited the expression of ECM components, proliferation of VSMCs and neointima formation in a carotid artery ligation model. Therefore, Shp2 is required for myocyte proliferation in cardiovascular development and vascular remodeling through TGFß1-regulated collagen synthesis.

The PSE1 gene modulates lead tolerance in Arabidopsis.

Lead (Pb) is a dangerous heavy metal contaminant with high toxicity to plants. However, the regulatory mechanism of plant Pb tolerance is poorly understood. Here, we showed that the PSE1 gene confers Pb tolerance in Arabidopsis. A novel Pb-sensitive mutant pse1-1 (Pb-sensitive1) was isolated by screening T-DNA insertion mutants. PSE1 encodes an unknown protein with an NC domain and was localized in the cytoplasm. PSE1 was induced by Pb stress, and the pse1-1 loss-of-function mutant showed enhanced Pb sensitivity; overexpression of PSE1 resulted in increased Pb tolerance. PSE1-overexpressing plants showed increased Pb accumulation, which was accompanied by the activation of phytochelatin (PC) synthesis and related gene expression. In contrast, the pse1-1 mutant showed reduced Pb accumulation, which was associated with decreased PC synthesis and related gene expression. In addition, the expression of PDR12 was also increased in PSE1-overexpressing plants subjected to Pb stress. Our results suggest that PSE1 regulates Pb tolerance mainly through glutathione-dependent PC synthesis by activating the expression of the genes involved in PC synthesis and at least partially through activating the expression of the ABC transporter PDR12/ABCG40.

Potential mechanisms and targeting strategies of the gut microbiota in antitumor immunity and immunotherapy.

BACKGROUND: Immunotherapies, notably immune checkpoints inhibitors that target programmed death 1/programmed death ligand 1(PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), had profoundly changed the way advanced and metastatic cancers are treated and dramatically improved overall and progression-free survival. AIMS: This review article aimed to explore the underlying molecular mechanisms by which the gut microbiota affects antitumor immunity and the efficacy of cancer immunotherapy. METHODS: We summarized the latest knowledge supporting the associations among the gut microbiota, antitumor immunity, and immunotherapy. Moreover, we disscussed the therapeutic strategy for improving immunotherapy efficacy by modulating gut microbiota in cancer treatment. RESULTS: The potential molecular mechanisms underlying these associations are explained in terms of four aspects: immunomodulation, molecular mimicry, mamps, and microbial metabolites. CONCLUSION: The gut microbiota significantly impacts antitumor immunity and alters the effectiveness of cancer immunotherapy.

Beyond ENO1, emerging roles and targeting strategies of other enolases in cancers.

Aerobic glycolysis is a hallmark property of cancer metabolism. Enolase is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate into phosphoenolpyruvate. In mammals, enolases exist in three isoforms, encoded by the genes ENO1, ENO2, and ENO3. The altered expression of enolases is a common occurrence in various types of cancer. Although most published studies on enolases have predominantly focused on the role of ENO1 in cancer, ENO2 and ENO3 have recently emerged as crucial regulatory molecules in cancer development. Significant progress has been made in understanding their multifaceted roles in oncogenesis. In this comprehensive review, we provide an overview of the structure, subcellular localization, diagnostic and prognostic significance, biological functions, and molecular mechanisms of ENO2 and ENO3 in cancer progression. The importance of enolase in cancer development makes it a novel therapeutic target for clinical applications. Furthermore, we discuss anticancer agents designed to target enolases and summarize their anticancer efficacy in both in vitro and in vivo studies.

ENO3 promotes colorectal cancer progression by enhancing cell glycolysis.

BACKGROUND: Colorectal cancer (CRC) is among the leading cause of cancer-related morbidity and mortality worldwide. Aerobic glycolysis, as a metabolic hallmark of cancer, plays an important role in CRC progression. Enolase 3 (ENO3) is a glycolytic enzyme that catalyzes 2-phosphoglycerate into phosphoenolpyruvate, while its role in CRC is still unknown. METHODS: Bioinformatics analysis was performed to examine the expression changes and roles of ENO3 in CRC patients from public databases. Then, ENO3 expression was validated in CRC tissues using Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) analysis, and western blot. Overexpression and silencing models were constructed using plasmid and lentivirus transfection. Cell viability, proliferation, and migration in vitro were applied to evaluate the protumoral effects of ENO3 on CRC. RNA sequencing and GO enrichment analysis of differentially expressed genes (DEGs) were performed to explore the underlying molecular mechanisms of ENO3 in CRC progression. The ATP and lactate production level were detected to assess cell glycolysis. RESULTS: ENO3 was significantly up-regulated in CRC. High ENO3 expression was positively correlated with poor prognosis and higher clinical stages of CRC patients. ROC curve demonstrated the diagnostic value of ENO3 for CRC with the AUC of 0.802. Gain- and loss-of function experiments demonstrated that ENO3 significantly enhanced the proliferation and migration ability of CRC cells in vitro. After ENO3 knockdown, RNA sequencing screened out a list of DEGs which were enriched in the regulation of the glycolytic process. The detection of lactate production and ATP level verified the role of ENO3 in the glycolytic process. CONCLUSION: Our findings illustrate that ENO3 could promote the progression of CRC by the enhancement of cell glycolysis, indicating the potential value of ENO3 as a novel biomarker and therapeutic target for CRC.

Predictive and Prognostic Assessment Models for Tumor Deposit in Colorectal Cancer Patients With No Distant Metastasis.

BACKGROUND: More and more evidence indicated that tumor deposit (TD) was significantly associated with local recurrence, distant metastasis (DM), and poor prognosis for patients with colorectal cancer (CRC). This study aims to explore the main clinical risk factors for the presence of TD in CRC patients with no DM (CRC-NDM) and the prognostic factors for TD-positive patients after surgery. METHODS: The data of patients with CRC-NDM between 2010 and 2017 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A logistic regression model was used to identify risk factors for TD presence. Fine and Gray's competing-risk model was performed to analyze prognostic factors for TD-positive CRC-NDM patients. A predictive nomogram was constructed using the multivariate logistic regression model. The concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and the calibration were used to evaluate the predictive nomogram. Also, a prognostic nomogram was built based on multivariate competing-risk regression. C-index, the calibration, and decision-curve analysis (DCA) were performed to validate the prognostic model. RESULTS: The predictive nomogram to predict the presence of TD had a C-index of 0.785 and AUC of 0.787 and 0.782 in the training and validation sets, respectively. From the competing-risk analysis, chemotherapy (subdistribution hazard ratio (SHR) = 0.542, p < 0.001) can significantly reduce CRC-specific death (CCSD). The prognostic nomogram for the outcome prediction in postoperative CRC-NDM patients with TD had a C-index of 0.727. The 5-year survival of CCSD was 17.16%, 36.20%, and 63.19% in low-, medium-, and high-risk subgroups, respectively (Gray's test, p < 0.001). CONCLUSIONS: We constructed an easily predictive nomogram in identifying the high-risk TD-positive CRC-NDM patients. Besides, a prognostic nomogram was built to help clinicians identify poor-outcome individuals in postoperative CRC-NDM patients with TD. For the high-risk or medium-risk subgroup, additional chemotherapy may be more advantageous for the TD-positive patients rather than radiotherapy.

METTL14 Regulates Intestine Cellular Senescence through m6A Modification of Lamin B Receptor.

N-6-Methyladenosine (m6A) modification is involved in multiple biological processes including aging. However, the regulation of m6A methyltransferase-like 14 (METTL14) in aging remains unclear. Here, we revealed that the level of m6A modification and the expression of METTL14 were particularly decreased in the intestine of aged mice as compared to young mice. Similar results were confirmed in Drosophila melanogaster. Knockdown of Mettl14 in Drosophila resulted in a short lifespan, associated disrupted intestinal integrity, and reduced climbing ability. In human CCD-18Co cells, knockdown of METTL14 accelerated cellular senescence, and the overexpression of METTL14 rescued senescent phenotypes. We also identified the lamin B receptor (LBR) as a target gene for METTL14-mediated m6A modification. Knockdown of METTL14 decreased m6A level of LBR, resulted in LBR mRNA instability, and thus induced cellular senescence. Our findings suggest that METTL14 plays an essential role in the m6A modification-dependent aging process via the regulation of LBR and provides a potential target for cellular senescence.

Emerging roles of lncRNA in cancer and therapeutic opportunities.

Cancer is difficult to cure due to frequent metastasis, and developing effective therapeutic approaches to treat cancer is urgently important. Long non-coding RNAs (lncRNAs) have diverse roles in regulating gene expression at both the transcriptional and translational levels and have been reported to be involved in tumorigenesis and tumor metastasis. In this article, we review the emerging roles of lncRNAs in cancer, especially in cancer immunity, cancer metabolism and cancer metastasis. We also discuss the use of novel technologies, such as antisense oligonucleotides, CRISPR-Cas9 and nanomedicines, to target lncRNAs and thus control cancers.