Advances in Engineered Macrophages: A New Frontier in Cancer Immunotherapy.

Macrophages, as pivotal cells within the tumour microenvironment, significantly influence the impact of and reactions to treatments for solid tumours. The rapid evolution of bioengineering technology has revealed the vast potential of engineered macrophages in immunotherapy, disease diagnosis, and tissue engineering. Given this landscape, the goal of harnessing and innovating macrophages as a novel strategy for solid tumour immunotherapy cannot be overstated. The diverse strategies for engineered macrophages in the realm of cancer immunotherapy, encompassing macrophage drug delivery systems, chimeric antigen receptor macrophage therapy, and synergistic treatment approaches involving bacterial outer membrane vesicles and macrophages, are meticulously examined in this review. These methodologies are designed to enhance the therapeutic efficacy of macrophages against solid tumours, particularly those that are drug-resistant and metastatic. Collectively, these immunotherapies are poised to supplement and refine current solid tumour treatment paradigms, thus heralding a new frontier in the fight against malignant tumours.

Targeting neutrophils: Mechanism and advances in cancer therapy.

BACKGROUND: Cancer is a thorny problem which cannot be conquered by mankind at present and recent researchers have put their focus on tumor microenviroment. Neutrophils, the prominent leukocytes in peripheral blood that accumulate in tumours, serves as frontline cells in response to tumour progression owing to the rapid development of micro biotechnology. Hence, targeted therapy with these neutrophils has made targeting treatment a promising field in cancer therapy. MAIN BODY: We broadly summarise some studies on the phenotypes and functions of tumour-associated neutrophils as well as the unique web-like products of neutrophils that play a role in cancer progression-neutrophil extracellular traps-and the interactions between neutrophils and the tumour microenvironment. Moreover, several targeted neutrophils therapeutic studies have made some progress and provided potential strategies for the treatment of cancer. CONCLUSION: This review aims to offer a holistic perspective on therapeutic interventions targeting neutrophils to further inspire more researches on cancer therapies.

Tumor neoantigens: Novel strategies for application of cancer immunotherapy.

Neoantigen-targeted immunotherapy is a rapidly advancing field that holds great promise for treating cancer. The recognition of antigens by immune cells is a crucial step in tumor-specific killing, and neoantigens generated by mutations in cancer cells possess high immunogenicity and are selectively expressed in tumor cells, making them an attractive therapeutic target. Currently, neoantigens find utility in various domains, primarily in the realm of neoantigen vaccines such as DC vaccines, nucleic acid vaccines, and synthetic long peptide vaccines. Additionally, they hold promise in adoptive cell therapy, encompassing tumor-infiltrating cells, T cell receptors, and chimeric antigen receptors which are expressed by genetically modified T cells. In this review, we summarized recent progress in the clinical use of tumor vaccines and adoptive cell therapy targeting neoantigens, discussed the potential of neoantigen burden as an immune checkpoint in clinical settings. With the aid of state-of-the-art sequencing and bioinformatics technologies, together with significant advancements in artificial intelligence, we anticipated that neoantigens will be fully exploited for personalized tumor immunotherapy, from screening to clinical application.

CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer.

Immune checkpoint blockade (ICB) is a promising treatment strategy for colorectal cancer (CRC) patients. However, most CRC patients do not response well to ICB therapy. Increasing evidence indicates that ferroptosis plays a critical role in immunotherapy. ICB efficacy may be enhanced by inducing tumor ferroptosis. Cytochrome P450 1B1 (CYP1B1) is a metabolic enzyme that participates in arachidonic acid metabolism. However, the role of CYP1B1 in ferroptosis remains unclear. In this study, we demonstrated that CYP1B1 derived 20-HETE activated the protein kinase C pathway to increase FBXO10 expression, which in turn promoted the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), ultimately inducing tumor cells resistance to ferroptosis. Furthermore, inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouce model. In addition, CYP1B1 expression was negatively correlated with ACSL4 expression, and high expression indicates poor prognosis in CRC. Taken together, our work identified CYP1B1 as a potential biomarker for enhancing anti-PD-1 therapy in CRC.

Targeting LAYN inhibits colorectal cancer metastasis and tumor-associated macrophage infiltration induced by hyaluronan oligosaccharides.

The accumulation of hyaluronan oligosaccharides (oHA) in colorectal cancer (CRC) is closely related to tumor metastasis, but the underlying mechanism remains unclear. In this study, we first described that LAYN, a novel HA receptor, was upregulated in CRC tissue. Aberrant LAYN expression correlated with CRC metastasis and poor prognosis and positively correlated with tumor-associated macrophage (TAM) infiltration and M2 macrophage polarization in the tumor environment. Both in vitro and in vivo studies demonstrated that LAYN is activated by oHA and subsequently induces CRC metastasis and macrophage infiltration. Mechanistic studies demonstrated that oHA activates LAYN by binding to the 60-68th amino acid region of the extracellular segment. oHA-induced LAYN activation promoted metastasis and CCL20 secretion through the NF-kB pathway in CRC cells. Furthermore, targeting LAYN using a blocking antibody prevented oHA-mediated tumor metastasis, TAM infiltration and M2 polarization. This study revealed the LAYN activation mechanism and identified a potential target for the treatment of CRC tumor exhibiting high oHA levels.

Identify a DNA Damage Repair Gene Signature for Predicting Prognosis and Immunotherapy Response in Cervical Squamous Cell Carcinoma.

The DNA damage repair (DDR) genes are increasingly gaining attention as potential therapeutic targets in cancers. In this study, we identified the DDR genes associated with the tumor mutation burden (TMB) and prognosis of cervical squamous cell carcinoma (CESC) based on The Cancer Genome Atlas (TCGA) database. Through LASSO Cox regression, the prognostic signature involving five DDR genes (ACTR2, TEX12, UBE2V1, HSF1, and FBXO6) was established, and the risk score was identified as an independent risk factor for CESC. The nomogram consisting of the five genes accurately predicted the overall survival (OS) and the immunotherapeutic response of CESC patients. Finally, the loss of the copies of the transcription factor (TF) SP140 in CESC patients may decrease the expression of FBXO6, improve DNA repair function, and reduce the diversity of neoantigens, thereby lowering the response to immunotherapies. Therefore, the DDR gene signature is a novel prognostic model and a biomarker for immunotherapies in CESC patients.

Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer.

Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors.

A Novel Ferroptosis-Related Gene Risk Signature for Predicting Prognosis and Immunotherapy Response in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer death worldwide with complicated molecular and cellular heterogeneity. Iron metabolism and ferroptosis play crucial roles in the pathogenesis of GC. However, the prognostic role and immunotherapy biomarker potential of ferroptosis-related genes (FRGs) in GC still remains to be clarified. METHODS: We comprehensively analyzed the prognosis of different expression FRGs, based on gastric carcinoma patients in the TCGA cohort. The functional enrichment and immune microenvironment associated with these genes in gastric cancer were investigated. The prognostic model was constructed to clarify the relation between FRGs and the prognosis of GC. Meanwhile, the ceRNA network of FRGs in the prognostic model was performed to explore the regulatory mechanisms. RESULTS: Gastric carcinoma patients were classified into the A, B, and C FRGClusters with different features based on 19 prognostic ferroptosis-related differentially expressed genes in the TCGA database. To quantify the FRG characteristics of individual patients, FRGScore was constructed. And the research shows the GC patients with higher FRGScore had worse survival outcome. Moreover, thirteen prognostic ferroptosis-related differentially expressed genes (DEGs) were selected to construct a prognostic model for GC survival outcome with a superior accuracy in this research. And we also found that FRG RiskScore can be an independent biomarker for the prognosis of GC patients. Interestingly, GC patients with lower RiskScore had less immune dysfunction and were more likely to respond to immunotherapy according to TIDE value analysis. Finally, a ceRNA network based on FRGs in the prognostic model was analyzed to show the concrete regulation mechanisms. CONCLUSIONS: The ferroptosis-related gene risk signature has a superior potent in predicting GC prognosis and acts as the biomarkers for immunotherapy, which may provide a reference in clinic.

Identification of a Novel Ferroptosis-Related Gene Prediction Model for Clinical Prognosis and Immunotherapy of Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common malignancies worldwide. Ferroptosis is a programmed, iron-dependent cell death observed in cancer cells. However, the prognostic potential and immunotherapy biomarker potential of ferroptosis-related genes (FRGs) in CRC patients remains to be clarified. METHODS: At first, we comprehensively analysed the different expression and prognosis of related FRGs in CRC patients based on TCGA cohort. The relationship between functional enrichment of these genes and immune microenvironment in CRC was investigated using the TCGA database. Prognostic model was constructed to determine the association between FRGs and the prognosis of CRC. Relative verification was done based on the GEO database. Meanwhile, the ceRNA network of FRGs in the model was also performed to explore the regulatory mechanisms. RESULTS: Eight differentially expressed FRGs were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the A, B, and C FRG clusters with different features. And FRG scores were constructed to quantify the FRG pattern of individual patients with colorectal cancer. The CRC patients with higher FRG score showed worse survival outcomes, higher immune dysfunction, and lower response to immunotherapy. The prognostic model showed a high accuracy for predicting the OS of CRC. Finally, a ceRNA network was analysed to show the concrete regulation mechanisms of critical FRGs in CRC. CONCLUSIONS: The FRG risk score prognostic model based on 8 FRGs exhibit superior predictive performance, providing a novel prognostic model with a high accuracy for CRC patients. Moreover, FRG score can be the potential biomarker of the response of immunotherapy for CRC.

Comprehensive Analysis of N6-Methyladenosine-Related lncRNA Signature for Predicting Prognosis and Immune Cell Infiltration in Patients with Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common tumor worldwide. Aberrant N6-methyladenosine (m6A) modification can influence the progress of the CRC. Additionally, long noncoding RNA (lncRNA) plays a critical role in CRC and has a close relationship with m6A modification. However, the prognostic potential of m6A-related lncRNAs in CRC patients still remains to be clarified. METHODS: We use "limma" R package, "glmnet" R package, and "survival" R package to screen m6A-related-lncRNAs with prognostic potential. Then, we comprehensively analysed and integrated the related lncRNAs in different TNM stages from TCGA database using the LASSO Cox regression. Meanwhile, the relationship between functional enrichment of m6A-related lncRNAs and immune microenvironment in CRC was also investigated using the TCGA database. A prognostic model was constructed and validated to determine the association between m6A-related lncRNAs in different TNM stages and the prognosis of CRC. RESULT: We demonstrated that three related m6A lncRNAs in different TNM stages were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the low-risk and the high-risk groups based on the expression of these lncRNAs. The patients in the low-risk group had longer overall survival than the patients in the high-risk group (P < 0.001). We further constructed and validated a prognostic nomogram based on these genes with a C-index of 0.80. The receiver operating characteristic curves confirmed the predictive capacity of the model. Meanwhile, we also found that the low-risk group has the correlation with the dendritic cell (DC). Finally, we discovered the relationship between the m6A regulators and the three lncRNAs. CONCLUSION: The prognostic model based on three m6A-related lncRNAs exhibits superior predictive performance, providing a novel prognostic model for the clinical evaluation of CRC patients.

Catheter ablation of premature ventricular complexes associated with false tendons: A case report.

BACKGROUND: False tendon is a common intraventricular anatomical variation. It refers to a fibroid or fibromuscular structure that exists in the ventricle besides the normal connection of papillary muscle and mitral or tricuspid valve. A large number of clinical studies have suggested that there is a significant correlation between false tendons and premature ventricular complexes. However, few studies have verified this correlation during radiofrequency catheter ablation of premature ventricular complexes. CASE SUMMARY: A 45-year-old male was admitted to receive radiofrequency ablation for symptomatic premature ventricular complexes. A three-dimensional model of the left ventricle was established by intracardiac echocardiography using the CartoSoundTM mapping system. In addition to the left anterior papillary muscle, the posterior papillary muscle was mapped. False tendons were found at the base of the interventricular septum, and the other end was connected to the left ventricular free wall near the apex. An irrigated touch force catheter was advanced into the left ventricle via the retrograde approach. The earliest activation site was marked at the interventricular septum attachment of the false tendons and was successfully ablated. CONCLUSION: This case verified that false tendons can cause premature ventricular complexes and may be cured by radiofrequency ablation guided by intracardiac echocardiography with the CartoSoundTM system.

The mouse autonomic nervous system modulates inflammation and epithelial renewal after corneal abrasion through the activation of distinct local macrophages.

Inflammation and reepithelialization after corneal abrasion are critical for the rapid restoration of vision and the prevention of microbial infections. However, the endogenous regulatory mechanisms are not completely understood. Here we report that the manipulation of autonomic nervous system (ANS) regulates the inflammation and healing processes. The activation of sympathetic nerves inhibited reepithelialization after corneal abrasion but increased the influx of neutrophils and the release of inflammatory cytokines. Conversely, the activation of parasympathetic nerves promoted reepithelialization and inhibited the influx of neutrophils and the release of inflammatory cytokines. Furthermore, we observed that CD64+CCR2+ macrophages in the cornea preferentially expressed the ß-2 adrenergic receptor (AR), whereas CD64+CCR2- macrophages preferentially expressed the α-7 nicotinic acetylcholine receptor (α7nAChR). After abrasion, the topical administration of a ß2AR agonist further enhanced the expression of the proinflammatory genes in the CD64+CCR2+ cell subset sorted from injured corneas. In contrast, the topical administration of an α7nAChR agonist further enhanced the expression of the anti-inflammatory genes in the CD64+CCR2- subset. Thus crosstalk between the ANS and local macrophage populations is necessary for the progress of corneal wound repair. Manipulation of ANS inputs to the wounded cornea may represent an alternative approach to the treatment of impaired wound healing.

Identification of breast cancer candidate genes using gene co-expression and protein-protein interaction information.

Breast cancer (BC) is one of the most common malignancies that could threaten female health. As the molecular mechanism of BC has not yet been completely discovered, identification of related genes of this disease is an important area of research that could provide new insights into gene function as well as potential treatment targets. Here we used subnetwork extraction algorithms to identify novel BC related genes based on the known BC genes (seed genes), gene co-expression profiles and protein-protein interaction network. We computationally predicted seven key genes (EPHX2, GHRH, PPYR1, ALPP, KNG1, GSK3A and TRIT1) as putative genes of BC. Further analysis shows that six of these have been reported as breast cancer associated genes, and one (PPYR1) as cancer associated gene. Lastly, we developed an expression signature using these seven key genes which significantly stratified 1660 BC patients according to relapse free survival (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.46-0.65; Logrank p = 5.5e-13). The 7-genes signature could be established as a useful predictor of disease prognosis in BC patients. Overall, the identified seven genes might be useful prognostic and predictive molecular markers to predict the clinical outcome of BC patients.

Xuezhikang, extract of red yeast rice, inhibited tissue factor and hypercoagulable state through suppressing nicotinamide adenine dinucleotide phosphate oxidase and extracellular signal-regulated kinase activation.

Xuezhikang, extract of red yeast rice, is a traditional Chinese medicine with multiple cardioprotective effect. It contains a family of naturally occurring statins, such as lovastatin. Tissue factor (TF) is overexpressed in macrophages of lipid core plaques, which display high procoagulant activity and seem to be a potentially target for anti-atherothrombosis. Therefore, the purpose of this study was to explore the effect and possible molecular mechanisms of xuezhikang on inhibiting TF expression and hypercoagulable state and the differences compared with lovastatin. Our results showed that xuezhikang significantly suppressed oxidized low-density lipoprotein-induced TF expression in macrophages in a concentration-dependent manner. Xuezhikang reduced nicotinamide adenine dinucleotide phosphate oxidase activity by decreasing membrane translocation of p47 through inhibition of extracellular signal-regulated kinase 1/2 activation. Nicotinamide adenine dinucleotide phosphate inhibitor (diphenyleneiodonium) also inhibited the oxidized low-density lipoprotein-induced TF expression, similar to the effects of xuezhikang. Furthermore, consistent with the severity of aortic atherosclerosis, xuezhikang (300 mg·kg·d) significantly reduced blood coagulation activation and TF expression in high-cholesterol diet-induced atherosclerotic rats. In addition, xuezhikang was more potent than lovastatin on inhibiting the expression of TF and nicotinamide adenine dinucleotide phosphate oxidase activation. These observations provide evidences that inhibition of xuezhikang on hypercoagulation and TF expression may partly account for its cardioprotective benefits.

[Effects of mixed-tocopherols and eicosapentaenoic acid on oxidized LDL-induced oxidative damage and inflammatory cytokine secretion in human umbilical vein endothelial cells].

OBJECTIVE: To observe the influence of either alone or combined mixed-tocopherols combined with eicosapentaenoic acid (EPA) and α-Tocopherol use on oxidized LDL (oxLDL) induced 8-hydroxy-2'-deoxyguanosine (8-OHDG) and interleukin-6 (IL-6) secretion by human umbilical vein endothelial cells (HUVECs) and to explore the potential mechanism. METHOD: Cultured HUVECs in vitro were incubated with oxLDL, oxLDL + α-tocopherol, oxLDL + mixed-tocopherols, oxLDL + EPA, oxLDL + α-tocopherol + EPA, oxLDL + mixed-tocopherols + EPA for 24 hours, respectively. Secretion of 8-OHDG and IL-6 were detected by cell enzyme linked immunosorbent assay (ELISA). The expressions of superoxide dismutase (SOD), protein kinase C-δ (PKC-δ), phosphorylated PKC-δ (p-PKC-δ) were analyzed by Western blot. RESULTS: 8-OHDG and IL-6 secretion of HUVECs was significantly increased significantly after incubated with oxLDL for 24 hours which could be significantly attenuated in the presence of tocopherols and EPA (alone or in combination, all P < 0.05) while the strongest inhibition effects were seen with combined use of mixed-tocopherols and EPA. Moreover, combination of mixed-tocopherols and EPA could also significantly increase SOD activity and decrease PKC activity (all P < 0.05). However, the protein expression of SOD and PKC-was similar among groups. CONCLUSION: Combined mixed-tocopherols + EPA use enhanced the inhibiting effects on the secretion of 8-OHDG and IL-6 in oxLDL stimulated HUVECs which might be linked with increased SOD activity and reduced p-PKC activity.