Suppression of protein quality control system by TRIM30a sensitises tumour cells to NK cell-mediated immune surveillance.

Tumorigenesis entails circumventing cell-intrinsic regulatory mechanisms while avoiding extrinsic immune surveillance and other host defence systems. Nevertheless, how tumour cells' ability to eliminate misfolded proteins affects immune surveillance remains poorly understood. In this study, we find that overexpression of murine tripartite motif-containing protein 30a (TRIM30a) sensitises tumour cells to natural killer (NK) cells-mediated cytolysis. TRIM30a has no effect on tumour cell proliferation or apoptosis in vitro. However, TRIM30a-overexpressing tumour cells grow substantially slower than control tumour cells in immune-competent mice but not in NK cell-depleted mice. [Correction added on 04 October 2023, after first online publication: 'NK-depleted' has been changed to 'NK cell-depleted' in the preceding sentence.] Mechanistically, TRIM30a overexpression impedes the clearance of misfolded proteins and increases the production of reactive oxygen species induced by proteotoxic stress, implying that TRIM30a impairs protein quality control (PQC) systems in tumour cells. Furthermore, TRIM30a reduces expression of genes encoding proteasome subunits and antioxidant proteins. Our study demonstrates that TRIM30a is a potential tumour suppressor and immune modulator that promotes tumour cytolysis by NK cells, and suggests that an enhanced PQC and antioxidant capacity is an integral part of the immune escape mechanism during tumorigenesis.

Natural Compounds, Optimal Combination of Brusatol and Polydatin Promote Anti-Tumor Effect in Breast Cancer by Targeting Nrf2 Signaling Pathway.

Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have made treatment options for TNBC more selective. However, there are still problems, such as poor patient tolerance, large administration doses, high dosing frequency, and toxic side effects, necessitating the development of more efficient and less toxic treatment strategies. High expression of Nrf2, a vital antioxidant transcription factor, often promotes tumor progression, and it is also one of the most effective targets in BC therapy. We found that in MDA-MB-231 cells and SUM159 cells, brusatol (BRU) combined with polydatin (PD) could significantly inhibit cell proliferation in vitro, significantly downregulate the expression of Nrf2 protein as well as the expression of downstream related target genes Heme Oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1), and promote reactive oxygen species (ROS) levels to further strengthen the anti-tumor effect. Furthermore, we discovered in our in vivo experiments that by reducing the drug dosage three times, we could significantly reduce tumor cell growth while avoiding toxic side effects, providing a treatment method with greater clinical application value for TNBC treatment.

TRIM family proteins: roles in proteostasis and neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs.

Artificial Intelligence and Machine Learning in Cancer Research: A Systematic and Thematic Analysis of the Top 100 Cited Articles Indexed in Scopus Database.

INTRODUCTION: Cancer is a major public health problem and a global leading cause of death where the screening, diagnosis, prediction, survival estimation, and treatment of cancer and control measures are still a major challenge. The rise of Artificial Intelligence (AI) and Machine Learning (ML) techniques and their applications in various fields have brought immense value in providing insights into advancement in support of cancer control. METHODS: A systematic and thematic analysis was performed on the Scopus database to identify the top 100 cited articles in cancer research. Data were analyzed using RStudio and VOSviewer.Var1.6.6. RESULTS: The top 100 articles in AI and ML in cancer received a 33 920 citation score with a range of 108 to 5758 times. Doi Kunio from the USA was the most cited author with total number of citations (TNC = 663). Out of 43 contributed countries, 30% of the top 100 cited articles originated from the USA, and 10% originated from China. Among the 57 peer-reviewed journals, the "Expert Systems with Application" published 8% of the total articles. The results were presented in highlight technological advancement through AI and ML via the widespread use of Artificial Neural Network (ANNs), Deep Learning or machine learning techniques, Mammography-based Model, Convolutional Neural Networks (SC-CNN), and text mining techniques in the prediction, diagnosis, and prevention of various types of cancers towards cancer control. CONCLUSIONS: This bibliometric study provides detailed overview of the most cited empirical evidence in AI and ML adoption in cancer research that could efficiently help in designing future research. The innovations guarantee greater speed by using AI and ML in the detection and control of cancer to improve patient experience.

Synergistic Tumor Cytolysis by NK Cells in Combination With a Pan-HDAC Inhibitor, Panobinostat.

Histone deacetylases (HDAC) are frequently overexpressed in tumors, and their inhibition has shown promising anti-tumor effects. However, the synergistic effects of HDAC inhibition with immune cell therapy have not been fully explored. Natural killer (NK) cells are cytotoxic lymphocytes for anti-tumor immune surveillance, with immunotherapy potential. We showed that a pan-HDAC inhibitor, panobinostat, alone demonstrated anti-tumor and anti-proliferative activities on all tested tumors in vitro. Additionally, panobinostat co-treatment or pretreatment synergized with NK cells to mediate tumor cell cytolysis. Mechanistically, panobinostat treatment increased the expression of cell adhesion and tight junction-related genes, promoted conjugation formation between NK and tumor cells, and modulates NK cell-activating receptors and ligands on tumor cells, contributing to the increased tumor cytolysis. Finally, panobinostat therapy led to better tumor control and synergized with anti-PD-L1 therapy. Our data highlights the anti-tumor potential of HDAC inhibition through tumor-intrinsic toxicity and enhancement of NK -based immunotherapy.

Exploiting the CRISPR-Cas9 gene-editing system for human cancers and immunotherapy.

The discovery of clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9) technology has brought advances in the genetic manipulation of eukaryotic cells, which has revolutionised cancer research and treatment options. It is increasingly being used in cancer immunotherapy, including adoptive T and natural killer (NK) cell transfer, secretion of antibodies, cytokine stimulation and overcoming immune checkpoints. CRISPR-Cas9 technology is used in autologous T cells and NK cells to express various innovative antigen designs and combinations of chimeric antigen receptors (CARs) targeted at specific antigens for haematological and solid tumors. Additionally, advanced engineering in immune cells to enhance their sensing circuits with sophisticated functionality is now possible. Intensive research on the CRISPR-Cas9 system has provided scientists with the ability to overcome the hostile tumor microenvironment and generate more products for future clinical use, especially off-the-shelf, universal cellular products, bringing exciting milestones for immunotherapy. This review discussed the application and challenges of CRISPR technology in cancer research and immunotherapy, its advances and prospects for promoting new cell-based therapeutic beyond immune oncology.

Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming.

The attachment of cells to the extracellular matrix (ECM) is the hallmark of structure-function stability and well-being. ECM detachment in localized tumors precedes abnormal dissemination of tumor cells culminating in metastasis. Programmed cell death (PCD) is activated during tumorigenesis to clear off ECM-detached cells through "anoikis." However, cancer cells develop several mechanisms for abrogating anoikis, thus promoting their invasiveness and metastasis. Specific factors, such as growth proteins, pH, transcriptional signaling pathways, and oxidative stress, have been reported as drivers of anoikis resistance, thus enhancing cancer proliferation and metastasis. Recent studies highlighted the key contributions of metabolic pathways, enabling the cells to bypass anoikis. Therefore, understanding the mechanisms driving anoikis resistance could help to counteract tumor progression and prevent metastasis. This review elucidates the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis. In addition, the authors have discussed other metabolic intermediates (especially amino acids and nucleotides) that are less explored, which could be crucial for anoikis resistance and metastasis.

A natural product, Piperlongumine (PL), increases tumor cells sensitivity to NK cell killing.

Natural Killer (NK) cells are components of innate immune surveillance against transformed cells. NK cell immunotherapy has attracted attention as a promising strategy for cancer treatment, whose antitumor effects, however, require further improvement. The use of small molecules with immunomodulatory potentials and selective tumor-killing possesses the potential to complement immunotherapy. This study demonstrated that Piperlongumine (PL), a natural alkaloid obtained from long pepper fruit, alone has antitumor and anti-proliferative potential on all the tested tumors in vitro. PL pretreatment of tumor cells also potentiates their susceptibility to NK cell cytolysis at the doses where NK cell functions were preserved. Importantly, PL suppresses both NK -sensitive MHC-I -deficient and MHC-I -sufficient tumor growth in vivo. Mechanistically, PL induces misfolded proteins, impedes autophagy, increases ROS and tumor conjugation with NK cells. Furthermore, PL enhances the expression of NK cell-activating receptors on NK cells and its ligands on tumor cells, possibly leading to increased susceptibility to NK cell killing. Our findings showed the antitumor and immunomodulatory potential of PL, which could be explored to complement NK cell immunotherapy for cancer treatment.

Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy.

Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy against the PD-1/PD-L1 axis, it induces sustained responses in a sizeable minority of cancer patients due to the activation of immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Inhibiting the immunosuppressive function of MDSCs is critical for successful cancer ICB therapy. Interestingly, lipid metabolism is a crucial factor in modulating MDSCs function. Fatty acid transport protein 2 (FATP2) conferred the function of PMN-MDSCs in cancer via the upregulation of arachidonic acid metabolism. However, whether regulating lipid accumulation in MDSCs by targeting FATP2 could block MDSCs reactive oxygen species (ROS) production and enhance PD-L1 blockade-mediated tumor immunotherapy remains unexplored. Here we report that FATP2 regulated lipid accumulation, ROS, and immunosuppressive function of MDSCs in tumor-bearing mice. Tumor cells-derived granulocyte macrophage-colony stimulating factor (GM-CSF) induced FATP2 expression in MDSCs by activation of STAT3 signaling pathway. Pharmaceutical blockade of FATP2 expression in MDSCs by lipofermata decreased lipid accumulation, reduced ROS, blocked immunosuppressive activity, and consequently inhibited tumor growth. More importantly, lipofermata inhibition of FATP2 in MDSCs enhanced anti-PD-L1 tumor immunotherapy via the upregulation of CD107a and reduced PD-L1 expression on tumor-infiltrating CD8+T-cells. Furthermore, the combination therapy blocked MDSC's suppressive role on T- cells thereby enhanced T-cell's ability for the production of IFN-γ. These findings indicate that FATP2 plays a key role in modulating lipid accumulation-induced ROS in MDSCs and targeting FATP2 in MDSCs provides a novel therapeutic approach to enhance anti-PD-L1 cancer immunotherapy.

Emerging Roles of Tripartite Motif-Containing Family Proteins (TRIMs) in Eliminating Misfolded Proteins.

Protein quality control (PQC) is pivotal for eukaryotic cells to eliminate misfolded proteins and maintain cellular homeostasis. A decreased or increased capacity of PQC is associated with various diseases, e.g., neurodegenerative diseases and cancers. Recently, increasing evidences have suggested that tripartite motif-containing family proteins (TRIMs) are the key players in PQC regulation. Most TRIMs are E3 ubiquitin ligases, such as TRIM11/19/25, which, through the ubiquitination modifications, can contribute to effectively remove the cellular misfolded proteins or protein aggregates via the UPS pathway. In this review, we summarized the participation of TRIM members in misfolded protein elimination through distinct pathways, including the ubiquitin-proteasome system (UPS), autophagy system, and ER-associated degradation (ERAD).

Lipid Metabolic Pathways Confer the Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Tumor.

Myeloid-derived suppressor cells (MDSCs) play crucial roles in tumorigenesis and their inhibition is critical for successful cancer immunotherapy. MDSCs undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation led by lipid accumulation in tumor. Increased exogenous fatty acid uptake by tumor MDSCs enhance their immunosuppressive activity on T-cells thus promoting tumor progression. Tumor-infiltrating MDSCs in mice may prefer FAO over glycolysis as a primary source of energy while treatment with FAO inhibitors improved anti-tumor immunity. This review highlights the immunosuppressive functions of lipid metabolism and its signaling pathways on MDSCs in the tumor microenvironment. The manipulation of these pathways in MDSCs is relevant to understand the tumor microenvironment therefore, could provide novel therapeutic approaches to enhance cancer immunotherapy.

Genetic reprogramming for NK cell cancer immunotherapy with CRISPR/Cas9.

Natural killer cells are potent cytotoxic lymphocytes specialized in recognizing and eliminating transformed cells, and in orchestrating adaptive anti-tumour immunity. However, NK cells are usually functionally exhausted in the tumour microenvironment. Strategies such as checkpoint blockades are under investigation to overcome NK cell exhaustion in order to boost anti-tumour immunity. The discovery and development of the CRISPR/Cas9 technology offer a flexible and efficient gene-editing capability in modulating various pathways that mediate NK cell exhaustion, and in arming NK cells with novel chimeric antigen receptors to specifically target tumour cells. Despite the high efficiency in its gene-editing capability, difficulty in the delivery of the CRISPR/Cas9 system remains a major bottleneck for its therapeutic applications, particularly for NK cells. The current review discusses feasible approaches to deliver the CRISPR/Cas9 systems, as well as potential strategies in gene-editing for NK cell immunotherapy for cancers.