Search

Background: Tumor cells develop multiple mechanisms to facilitate their immune evasion. Identifying tumor-intrinsic factors that support immune evasion may provide new strategies for cancer immunotherapy. We aimed to explore the function and the mechanism of the tumor-intrinsic factor NPM1, a multifunctional nucleolar phosphoprotein, in cancer immune evasion and progression. Methods: The roles of NPM1 in tumor progression and tumor microenvironment (TME) reprogramming were examined by subcutaneous inoculation of Npm1-deficient tumor cells into syngeneic mice, and then explored by CyTOF, flow cytometry, immunohistochemistry staining, and RNA-seq. The in-vitro T-cell killing of OVA-presenting tumor cells by OT-1 transgenic T cells was observed. The interaction of NPM1 and IRF1 was verified by Co-IP. The regulation of NPM1 in IRF1 DNA binding to Nlrc5, Ciita promoter was determined by dual-luciferase reporter assay and ChIP-qPCR. Results: High levels of NPM1 expression predict low survival rates in various human tumors. Loss of NPM1 inhibited tumor progression and enhanced the survival of tumor-bearing mice. Npm1-deficient tumors showed increased CD8+ T cell infiltration and activation alongside the reduced presence of immunosuppressive cells. Npm1 deficiency increased MHC-I and MHC-II molecules and specific T-cell killing. Mechanistically, NPM1 associates with the transcription factor IRF1 and then sequesters IRF1 from binding to the Nlrc5 and Ciita promoters to suppress IRF1-mediated expression of MHC-I and MHC-II molecules in tumor cells. Conclusions: Tumor-intrinsic NPM1 promotes tumor immune evasion via suppressing IRF1-mediated antigen presentation to impair tumor immunogenicity and reprogram the immunosuppressive TME. Our study identifies NPM1 as a potential target for improving cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Trichinella spiralis (T. spiralis) is a parasitic helminth that causes a globally prevalent neglected zoonotic disease, and worms at different developmental stages (muscle larvae, adult worms, newborn larvae) induce immune attack at different infection sites, causing serious harm to host health. Several innate immune cells release extracellular traps (ETs) to entrap and kill most pathogens that invade the body. In response, some unicellular pathogens have evolved a strategy to escape capture by ETs through the secretion of nucleases, but few related studies have investigated multicellular helminths. Results: In the present study, we observed that ETs from neutrophils capture adult worms of T. spiralis, while ETs from macrophages trap muscle larvae and newborn larvae, and ETs had a killing effect on parasites in vitro. To defend against this immune attack, T. spiralis secretes plancitoxin-1, a DNase II-like protein, to degrade ETs and escape capture, which is essential for the survival of T. spiralis in the host. Conclusions: In summary, these findings demonstrate that T. spiralis escapes ET-mediated capture by secreting deoxyribonuclease as a potential conserved immune evasion mechanism, and plancitoxin-1 could be used as a potential vaccine candidate. [ABSTRACT FROM AUTHOR]

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is a common and important post-translational modification (PTM) linking O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues in proteins. Extensive research indicates its impact on target protein stability, activity, and interactions. O-linked N-acetylglucosamine transferase (OGT) is a critical enzyme that catalyzes O-GlcNAc modification, responsible for adding O-GlcNAc to proteins. OGT and O-GlcNAcylation are overexpressed in many tumors and closely associated with tumor growth, invasion, metabolism, drug resistance, and immune evasion. This review delineates the biochemical functions of OGT and summarizes its effects and mechanisms in tumors. Targeting OGT presents a promising novel approach for treating human malignancies. [ABSTRACT FROM AUTHOR]

Tumor cells possess complex immune evasion mechanisms to evade immune system attacks, primarily through metabolic reprogramming, which significantly alters the tumor microenvironment (TME) to modulate immune cell functions. When a tumor is sufficiently immunogenic, it can activate cytotoxic T-cells to target and destroy it. However, tumors adapt by manipulating their metabolic pathways, particularly glucose, amino acid, and lipid metabolism, to create an immunosuppressive TME that promotes immune escape. These metabolic alterations impact the function and differentiation of non-tumor cells within the TME, such as inhibiting effector T-cell activity while expanding regulatory T-cells and myeloid-derived suppressor cells. Additionally, these changes lead to an imbalance in cytokine and chemokine secretion, further enhancing the immunosuppressive landscape. Emerging research is increasingly focusing on the regulatory roles of non-tumor cells within the TME, evaluating how their reprogrammed glucose, amino acid, and lipid metabolism influence their functional changes and ultimately aid in tumor immune evasion. Despite our incomplete understanding of the intricate metabolic interactions between tumor and non-tumor cells, the connection between these elements presents significant challenges for cancer immunotherapy. This review highlights the impact of altered glucose, amino acid, and lipid metabolism in the TME on the metabolism and function of non-tumor cells, providing new insights that could facilitate the development of novel cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Background: Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. Methods: The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. Results: APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. Conclusions: APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma. [ABSTRACT FROM AUTHOR]

During tumorigenesis and progression, the immune checkpoint programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) play critical roles in suppressing T cell-mediated anticancer immune responses, leading to T-cell exhaustion and subsequent tumor evasion. Therefore, anti-PD-L1/PD-1 therapy has been an attractive strategy for treating cancer over the past decade. However, the overall efficacy of this approach remains suboptimal, revealing an urgent need for novel insights. Interestingly, increasing evidence indicates that both PD-L1 on tumor cells and PD-1 on tumor-specific T cells undergo extensive N-linked glycosylation, which is essential for the stability and interaction of these proteins, and this modification promotes tumor evasion. In various preclinical models, targeting the N-linked glycosylation of PD-L1/PD-1 was shown to significantly increase the efficacy of PD-L1/PD-1 blockade therapy. Furthermore, deglycosylation of PD-L1 strengthens the signal intensity in PD-L1 immunohistochemistry (IHC) assays, improving the diagnostic and therapeutic relevance of this protein. In this review, we provide an overview of the regulatory mechanisms underlying the N-linked glycosylation of PD-L1/PD-1 as well as the crucial role of N-linked glycosylation in PD-L1/PD-1-mediated immune evasion. In addition, we highlight the promising implications of targeting the N-linked glycosylation of PD-L1/PD-1 in the clinical diagnosis and treatment of cancer. Our review identifies knowledge gaps and sheds new light on the cancer research field. [ABSTRACT FROM AUTHOR]

A century ago, the Warburg effect was first proposed, revealing that cancer cells predominantly rely on glycolysis during the process of tumorigenesis, even in the presence of abundant oxygen, shifting the main pathway of energy metabolism from the tricarboxylic acid cycle to aerobic glycolysis. Recent studies have unveiled the dynamic transfer of mitochondria within the tumor microenvironment, not only between tumor cells but also between tumor cells and stromal cells, immune cells, and others. In this review, we explore the pathways and mechanisms of mitochondrial transfer within the tumor microenvironment, as well as how these transfer activities promote tumor aggressiveness, chemotherapy resistance, and immune evasion. Further, we discuss the research progress and potential clinical significance targeting these phenomena. We also highlight the therapeutic potential of targeting intercellular mitochondrial transfer as a future anti-cancer strategy and enhancing cell-mediated immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. Methods: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. Results: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. Conclusions: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT. [ABSTRACT FROM AUTHOR]

Background: In prostate cancer (PCa), well-established biomarkers such as MSI status, TMB high, and PDL1 expression serve as reliable indicators for favorable responses to immunotherapy. Recent studies have suggested a potential association between CDK12 mutations and immunotherapy response; however, the precise mechanisms through which CDK12 mutation may influence immune response remain unclear. A plausible explanation for immune evasion in this subset of CDK12-mutated PCa may be reduced MHC expression. Results: Using genomic data of CDK12-mutated PCa from 48 primary and 10 metastatic public domain samples and a retrospective cohort of 53 low-intermediate risk primary PCa, we investigated how variation in the expression of the MHC genes affected associated downstream pathways. We classified the patients based on gene expression quartiles of MHC-related genes and categorized the tumors into "High" and "Low" expression levels. CDK12-mutated tumors with higher MHC-expressed pathways were associated with the immune system and elevated PD-L1, IDO1, and TIM3 expression. Consistent with an inflamed tumor microenvironment (TME) phenotype, digital cytometric analyses identified increased CD8 + T cells, B cells, γδ T cells, and M1 Macrophages in this group. In contrast, CDK12-mutated tumors with lower MHC expression exhibited features consistent with an immune cold TME phenotype and immunoediting. Significantly, low MHC expression was also associated with chromosome 6 loss of heterozygosity (LOH) affecting the entire HLA gene cluster. These LOH events were observed in both major clonal and minor subclonal populations of tumor cells. In our retrospective study of 53 primary PCa cases from this Institute, we found a 4% (2/53) prevalence of CDK12 mutations, with the confirmation of this defect in one tumor through Sanger sequencing. In keeping with our analysis of public domain data this tumor exhibited low MHC expression at the RNA level. More extensive studies will be required to determine whether reduced HLA expression is generally associated with primary tumors or is a specific feature of CDK12 mutated PCa. Conclusions: These data show that analysis of CDK12 alteration, in the context of MHC expression levels, and LOH status may offer improved predictive value for outcomes in this potentially actionable genomic subgroup of PCa. In addition, these findings highlight the need to explore novel therapeutic strategies to enhance MHC expression in CDK12-defective PCa to improve immunotherapy responses. [ABSTRACT FROM AUTHOR]

Background: Disulfidptosis is a novel form of programmed cell death induced by high SLC7A11 expression under glucose starvation conditions, unlike other known forms of cell death. However, the roles of disulfidptosis in cancers have yet to be comprehensively well-studied, particularly in ccRCC. Methods: The expression profiles and somatic mutation of DGs from the TCGA database were investigated. Two DGs clusters were identified by unsupervised consensus clustering analysis, and a disulfidptosis-related prognostic signature (DR score) was constructed. Furthermore, the predictive capacity of the DR score in prognosis was validated by several clinical cohorts. We also developed a nomogram based on the DR score and clinical features. Then, we investigated the differences in the clinicopathological information, TMB, tumor immune landscapes, and biological characteristics between the high- and low-risk groups. We evaluated whether the DR score is a robust tool for predicting immunotherapy response by the TIDE algorithm, immune checkpoint genes, submap analysis, and CheckMate immunotherapy cohort. Results: We identified two DGs clusters with significant differences in prognosis, tumor immune landscapes, and clinical features. The DR score has been demonstrated as an independent risk factor by several clinical cohorts. The high-risk group patients had a more complicated tumor immune microenvironment and suffered from more tumor immune evasion in immunotherapy. Moreover, patients in the low-risk group had better prognosis and response to immunotherapy, particularly in anti-PD1 and anti-CTLA-4 inhibitors, which were verified in the CheckMate immunotherapy cohort. Conclusion: The DR score can accurately predict the prognosis and immunotherapy response and assist clinicians in providing a personalized treatment regime for ccRCC patients. [ABSTRACT FROM AUTHOR]

Background: Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality and poor prognosis. Important function invests circRNAs with tremendous potential in biomarkers and therapeutic targets. Nevertheless, it is still unknown how circRNAs contribute to the evolution of ICC. Methods: CircRNAs in paired ICC and adjacent tissues were screened by circRNAs sequencing. To explore the impact of circRNAs on ICC development, experiments involving gain and loss of function were conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, RNA pull-down, chromatin immunoprecipitation (ChIP), ubiquitination assays and so on were employed to identify the molecular regulatory role of circRNAs. Results: Herein, we reported a new circRNA, which originates from exon 9 to exon 15 of the SLCO1B3 gene (named circSLCO1B3), orchestrated ICC progression by promoting tumor proliferation, metastasis and immune evasion. We found that the circSLCO1B3 gene was highly overexpressed in ICC tissues and related to lymphatic metastasis, tumor sizes, and tumor differentiation. Mechanically, circSLCO1B3 not only promoted ICC proliferation and metastasis via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity via suppressing ubiquitin-proteasome-dependent degradation of PD-L1 by E3 ubiquitin ligase SPOP. We further found that methyltransferase like 3 (METTL3) mediated the m6A methylation of circSLCO1B3 and stabilizes its expression. Our findings indicate that circSLCO1B3 is a potential prognostic marker and therapeutic target in ICC patients. Conclusions: Taken together, m6A-modified circSLCO1B3 was correlated with poor prognosis in ICC and promoted ICC progression not only by enhancing proliferation and metastasis via potentiating HOXC8 expression, but also by inducing immune evasion via antagonizing PD-L1 degradation. These results suggest that circSLCO1B3 is a potential prognostic marker and therapeutic target for ICC. [ABSTRACT FROM AUTHOR]

Since the emergence of SARS-CoV-2, different variants and subvariants successively emerged to dominate global virus circulation as a result of immune evasion, replication fitness or both. COVID-19 vaccines continue to be updated in response to the emergence of antigenically divergent viruses, the first being the bivalent RNA vaccines that encodes for both the Wuhan-like and Omicron BA.5 subvariant spike proteins. Repeated infections and vaccine breakthrough infections have led to complex immune landscapes in populations making it increasingly difficult to assess the intrinsic neutralizing antibody responses elicited by the vaccines. Hong Kong's intensive COVID-19 containment policy through 2020–2021 permitted us to identify sera from a small number of infection-naïve individuals who received 3 doses of the RNA BNT162b2 vaccine encoding the Wuhan-like spike (WT) and were boosted with a fourth dose of the WT vaccine or the bivalent WT and BA.4/5 spike (WT + BA.4/5). While neutralizing antibody to wild-type virus was comparable in both vaccine groups, BNT162b2 (WT + BA.4/BA.5) bivalent vaccine elicited significantly higher plaque neutralizing antibodies to Omicron subvariants BA.5, XBB.1.5, XBB.1.16, XBB.1.9.1, XBB.2.3.2, EG.5.1, HK.3, BA.2.86 and JN.1, compared to BNT162b2 monovalent vaccine. The single amino acid substitution that differentiates the spike of JN.1 from BA.2.86 resulted in a profound antigenic change. [ABSTRACT FROM AUTHOR]

Background: Emerging evidences suggest that aberrant metabolites contributes to the immunosuppressive microenvironment that leads to cancer immune evasion. Among tumor immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) are pathologically activated and extremely immunosuppressive, which are closely associated with poor clinical outcomes of cancer patients. However, the correlation between MDSCs mediated immunosuppression and particular cancer metabolism remained elusive. Methods: Spontaneous lung adenocarcinoma and subcutaneous mouse tumor models, gas chromatography–mass spectrometry (GC–MS) and immunofluorescence assay of patient-derived lung adenocarcinoma tissues, and flow cytometry, RNA sequencing and Western blotting of immune cells, were utilized. Results: Metabolite profiling revealed a significant accumulation of acetic acids in tumor tissues from both patients and mouse model, which contribute to immune suppression and cancer progression significantly through free fatty acid receptor 2 (FFAR2). Furthermore, FFAR2 is highly expressed in the myeloid-derived suppressor cells (MDSCs) from the tumor of lung adenocarcinoma (LUAD) patients which is greatly associated with poor prognosis. Surprisingly, whole or myeloid Ffar2 gene deletion markedly inhibited urethane-induced lung carcinogenesis and syngeneic tumor growth with reduced MDSCs and increased CD8+ T cell infiltration. Mechanistically, FFAR2 deficiency in MDSCs significantly reduced the expression of Arg1 through Gαq/Calcium/PPAR-γ axis, which eliminated T cell dysfunction through relieving L-Arginine consumption in tumor microenvironment. Therefore, replenishment of L-Arginine or inhibition to PPAR-γ restored acetic acids/FFAR2 mediated suppression to T cells significantly. Finally, FFAR2 inhibition overcame resistance to immune checkpoint blockade through enhancing the recruitment and cytotoxicity of tumor-infiltrating T cells. Conclusion: Altogether, our results demonstrate that the acetic acids/FFAR2 axis enhances MDSCs mediated immunosuppression through Gαq/calcium/PPAR-γ/Arg1 signaling pathway, thus contributing to cancer progression. Therefore, FFAR2 may serve as a potential new target to eliminate pathologically activated MDSCs and reverse immunosuppressive tumor microenvironment, which has great potential in improving clinical outcomes of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: LATS1/2 are frequently mutated and down-regulated in endometrial cancer (EC), but the contributions of LATS1/2 in EC progression remains unclear. Impaired antigen presentation due to mutations or downregulation of the major histocompatibility complex class I (MHC-I) has been implicated in tumor immune evasion. Herein, we elucidate the oncogenic role that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I. Methods: The mutation and expression as well as the clinical significance of LATS1/2 in EC was assessed in the TCGA cohort and our sample cohort. CRISPR-Cas9 was used to construct knockout cell lines of LATS1/2 in EC. Differentially expressed genes were analyzed by RNA-seq. The interaction between LATS1/2 and STAT1 was verified using co-immunoprecipitation and GST pull-down assays. Mass spectrometry, in vitro kinase assays, ChIP-qPCR, flow cytometry, immunohistochemistry, immunofluorescence and confocal microscopy were performed to investigate the regulation of LATS1/2 on MHC-I through interaction with and phosphorylate STAT1. The killing effect of activated PBMCs on EC cells were used to monitor anti-tumor activity. Results: Here, we demonstrate that LATS1/2 are frequently mutated and down-regulated in EC. Moreover, LATS1/2 loss was found to be associated with a significant down-regulation of MHC-I, independently of the Hippo-YAP pathway. Instead, LATS1/2 were found to directly interact with and phosphorylate STAT1 at Ser727, a crucial transcription factor for MHC-I upregulation in response to interferon-gamma (IFN-γ) signaling, to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, the loss of LATS1/2 was observed to confer increased resistance of EC cells to immune cell-mediated killing and this resistance could be reversed by over-expression of MHC-I. Conclusion: Our findings indicate that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I, leading to the suppression of infiltrating activated CD8 + T cells and highlight the importance of LATS1/2 in IFN-γ signaling-mediated tumor immune response, suggesting that LATS1/2 is a promising target for immune checkpoint blockade therapy in EC. [ABSTRACT FROM AUTHOR]

Background: A minute fraction of patients stands to derive substantial benefits from immunotherapy, primarily attributable to immune evasion. Our objective was to formulate a predictive signature rooted in genes associated with cytotoxic T lymphocyte evasion (CERGs), with the aim of predicting outcomes and discerning immunotherapeutic response in colorectal cancer (CRC). Methods: 101 machine learning algorithm combinations were applied to calculate the CERGs prognostic index (CERPI) under the cross−validation framework, and patients with CRC were separated into high− and low−CERPI groups. Relationship between immune cell infiltration levels, immune−related scores, malignant phenotypes and CERPI were further analyzed. Various machine learning methods were used to identify key genes related to both patient survival and immunotherapy benefits. Expression of HOXC6, G0S2, and MX2 was evaluated and the effects of HOXC6 and G0S2 on the viability and migration of a CRC cell line were in−vitro verified. Results: The CERPI demonstrated robust prognostic efficacy in predicting the overall survival of CRC patients, establishing itself as an independent predictor of patient outcomes. The low−CERPI group exhibited elevated levels of immune cell infiltration and lower scores for tumor immune dysfunction and exclusion, indicative of a greater potential benefit from immunotherapy. Moreover, there was a positive correlation between CERPI levels and malignant tumor phenotypes, suggesting that heightened CERPI expression contributes to both the occurrence and progression of tumors. Thirteen key genes were identified, and their expression patterns were scrutinized through the analysis of single−cell datasets. Notably, HOXC6, G0S2, and MX2 exhibited upregulation in both CRC cell lines and tissues. Subsequent knockdown experiments targeting G0S2 and HOXC6 resulted in a significant suppression of CRC cell viability and migration. Conclusion: We developed the CERPI for effectively predicting survival and response to immunotherapy in patients, and these results may provide guidance for CRC diagnosis and precise treatment. [ABSTRACT FROM AUTHOR]

Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges. [ABSTRACT FROM AUTHOR]

Exosomes are small vesicles of endosomal origin that are released by almost all cell types, even those that are pathologically altered. Exosomes widely participate in cell-to-cell communication via transferring cargo, including nucleic acids, proteins, and other metabolites, into recipient cells. Tumour-derived exosomes (TDEs) participate in many important molecular pathways and affect various hallmarks of cancer, including fibroblasts activation, modification of the tumour microenvironment (TME), modulation of immune responses, angiogenesis promotion, setting the pre-metastatic niche, enhancing metastatic potential, and affecting therapy sensitivity and resistance. The unique exosome biogenesis, composition, nontoxicity, and ability to target specific tumour cells bring up their use as promising drug carriers and cancer biomarkers. In this review, we focus on the role of exosomes, with an emphasis on their protein cargo, in the key mechanisms promoting cancer progression. We also briefly summarise the mechanism of exosome biogenesis, its structure, protein composition, and potential as a signalling hub in both normal and pathological conditions. A1Dxc4hLEvJAjvXsZVsCuz Video Abstract [ABSTRACT FROM AUTHOR]

Background: The dynamic interaction between cancer cells and tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is an active barrier to the effector arm of the antitumour immune response. Cancer-secreted exosomes are emerging mediators of this cancer-stromal cross-talk in the TME; however, the mechanisms underlying this interaction remain unclear. Methods: Exosomes were isolated with ExoQuick exosome precipitation solution. The polarizing effect of TAMs was evaluated by flow cytometry, western blot analysis, immunofluorescence staining and in vitro phagocytosis assays. Clinical cervical cancer specimens and an in vivo xenograft model were also employed. Results: Our previous study showed that hypoxia increased the expression of ZEB1 in cervical squamous cell carcinoma (CSCC) cells, which resulted in increased infiltration of TAMs. Here, we found that hypoxia-induced ZEB1 expression is closely correlated with CD47-SIRPα axis activity in CSCC, which enables cancer cells to evade phagocytosis by macrophages and promotes tumour progression. ZEB1 was found to directly activate the transcription of the CD47 gene in hypoxic CSCC cells. We further showed that endogenous ZEB1 was characteristically enriched in hypoxic CSCC cell-derived exosomes and transferred into macrophages via these exosomes to promote SIRPα+ TAM polarization. Intriguingly, exosomal ZEB1 retained transcriptional activity and reprogrammed SIRPα+ TAMs via activation of the STAT3 signalling pathway in vitro and in vivo. STAT3 inhibition reduced the polarizing effect induced by exosomal ZEB1. Knockdown of ZEB1 increased the phagocytosis of CSCC cells by macrophages via decreasing CD47 and SIRPα expression. Conclusions: Our results suggest that hypoxia-induced ZEB1 promotes immune evasion in CSCC by strengthening the CD47-SIRPα axis. ZEB1-targeted therapy in combination with CD47-SIRPα checkpoint immunotherapy may improve the outcomes of CSCC patients in part by disinhibiting innate immunity. [ABSTRACT FROM AUTHOR]

Background: Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (IO/TKI) have been recently recommended as standard first-line therapy for advanced renal cell carcinoma, while no clinical-available biomarker has been applied. This study aimed to investigate the associations between RUNX3 pathway signature and IO/TKI benefits in renal cell carcinoma (RCC). Methods: Two IO/TKI cohorts (ZS-MRCC, JAVELIN-101) and one high-risk localized RCC cohort (ZS-HRRCC) were included. All samples were evaluated by RNA-sequencing, and RUNX Family Transcription Factor 3 (RUNX3) pathway were determined by single sample gene set enrichment analysis. Flow cytometry were applied for immune cell infiltration and function. Results: RUNX3 signature was elevated in RCC samples, compared non-tumor tissues (P < 0.001). High-RUNX3 signature was associated with shorter progression-free survival (PFS) in both IO/TKI cohorts (ZS-MRCC cohort, P = 0.025; JAVELIN-101 cohort, P = 0.019). RUNX3 signature also predicted IO/TKI benefit in advanced RCC, compared with TKI monotherapy (interaction p = 0.027). RUNX3 signature was associated with decreased number of GZMB + CD8 + T cells (Spearman's ρ=-0.42, P = 0.006), and increased number of PD1 + CD8 + T cells (Spearman's ρ = 0.29, P = 0.072). Moreover, the integration of RUNX3 signature and GZMB expression showed predictive potential for TKI/IO (log-rank P < 0.001). In addition, the predictive value of RUNX3 signature for IO/TKI benefit was restricted in SETD2-wild type patients (log-rank P < 0.001). Finally, a risk score was established by random forest for IO/TKI benefit, showing remarkable predictive potency (Log-rank P < 0.001). Conclusions: RUNX3 pathway signature could be a potential predictive biomarker for IO/TKI treatment in advanced RCC, for both prognosis and treatment selection between IO/TKI and TKI monotherapy. [ABSTRACT FROM AUTHOR]

Background: The occurrence of epithelial-mesenchymal transition (EMT) and immune evasion is considered to contribute to poor prognosis in lung adenocarcinoma (LUAD). Therefore, this study aims to explore the key oncogenes that promote EMT and immune evasion and reveal the expression patterns, prognostic value, and potential biological functions. Methods: Firstly, we identified gene modules associated with EMT and Tumor Immune Dysfunction and Exclusion (TIDE) through weighted gene co-expression network analysis (WGCNA). Next, we utilized differential analysis and machine learning to identify the key genes and validate them. Moreover, we analyzed the correlation between key genes and tumor microenvironment remodeling, drug sensitivity, as well as mutation frequency. Furthermore, we explored and validated their malignant biological characteristics through in vitro experiments and clinical samples. Finally, potential drugs for LUAD were screened based on CMap and validated through experiments. Results: Firstly, WGCNA analysis revealed that red and green modules were highly correlated with EMT and TIDE. Among them, upregulated expression of SPOCK1 was observed in lung adenocarcinoma tissues and was associated with poor prognosis. Additionally, patients in the high SPOCK1 group showed more activation of malignant oncogenic pathways, higher infiltration of immunosuppressive components, and a higher frequency of mutations. The knockdown of SPOCK1 suppressed invasion and metastasis capabilities of lung adenocarcinoma cells, and the high expression of SPOCK1 was associated with low infiltration of CD8+ T cells. Therapeutic aspects, SPOCK1 can be a candidate indicator for drug sensitivity and CMap showed that VER-155008 was the drug candidate with the largest perturbation effect on the SPOCK1 expression profile. In vitro and in vivo experiments validated the cancer-inhibitory effect of VER-155008 in LUAD. Conclusion: This study revealed through comprehensive bioinformatics analysis and experimental analysis that SPOCK1 can promote EMT and immune escape in LUAD, and it may serve as a promising candidate prognostic biomarker and therapeutic target for LUAD. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Similar to other types of tumors, GC cells undergo metabolic reprogramming and switch to a "predominantly glycolytic" metabolic pattern to promote its survival and metastasis, also known as "the Warburg effect", which is characterized by enhanced glucose uptake and lactate production. A large number of studies have shown that targeting cancer cells to enhanced glycolysis is a promising strategy, that can make cancer cells more susceptible to other conventional treatment methods of treatment, including chemotherapy, radiotherapy and immunotherapy, and so on. Therefore, this review summarizes the metabolic characteristics of glycolysis in GC cells and focuses on how abnormal lactate concentration can lead to immunosuppression through its effects on the differentiation, metabolism, and function of infiltrating immune cells, and how targeting this phenomenon may be a potential strategy to improve the therapeutic efficacy of GC. [ABSTRACT FROM AUTHOR]

Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance. [ABSTRACT FROM AUTHOR]

The LuxS quorum sensing system is a widespread system employed by many bacteria for cell-to-cell communication. The luxS gene has been demonstrated to play a crucial role in intramacrophage survival of piscine Streptococcus agalactiae, but the underlying mechanism remains largely unknown. In this study, transcriptome analysis, followed by the luxS gene deletion and subsequent functional studies, confirmed that impaired bacterial survival inside macrophages due to the inactivation of luxS was associated with reduced transcription of the fruRKI operon, encoding the fructose-specific phosphotransferase system. Further, luxS was determined not to enhance the transcription of fruRKI operon by binding its promoter, but to upregulate the expression of this operon via affecting the binding ability of catabolite control protein A (CcpA) to the catabolite responsive element (cre) in the promoter of fruRKI. Collectively, our study identifies a novel and previously unappreciated role for luxS in bacterial intracellular survival, which may give a more thorough understanding of the immune evasion mechanism in S. agalactiae. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade (ICB) represents a revolutionary advance in cancer treatment but remains limited success in triple-negative breast cancer (TNBC). Here we aim to explore the mechanism of RNA-binding protein (RBP) HuR in cancer immune evasion by post-transcriptionally regulating PD-L1 and evaluate the potential of HuR inhibition to improve immune response. Methods: The binding between HuR and PD-L1 mRNA was determined by ribonucleoprotein immunoprecipitation and RNA pull-down assays. The HuR knockout clones were established by CRISPR/Cas9 technology. The protein levels were assessed by Western blot, immunohistochemistry, and immunocytochemistry. The function and molecular mechanism of HuR-PD-L1 were determined by in vitro T cell activation and killing assay and in vivo efficacy assay. Results: We found that HuR directly bound to and stabilized PD-L1 mRNA. Knocking out HuR reduced PD-L1 levels and promoted T cell activation. We discovered that niclosamide reduced PD-L1 by inhibiting HuR cytoplasmic translocation, and diminished glycosylation of PD-L1. Niclosamide enhanced T cell-mediated killing of cancer cells and significantly improved the efficacy of anti-PD-1 immunotherapy in two syngeneic animal tumor models. Conclusion: We identified HuR as a novel posttranscriptional regulator of PD-L1, which plays an important role in tumor immune evasion. Niclosamide might be a promising repurposed drug to improve the patient response to immunotherapy by targeting HuR-PD-L1 axis. Our study demonstrates a novel strategy for targeting HuR/PD-L1 and provides the first proof-of-principle for repurposing niclosamide as a HuR inhibitor to overcome cancer immune evasion and improve response to ICB immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment. [ABSTRACT FROM AUTHOR]

Innate immunity is the first line of the host immune system to fight against infections. Natural killer cells are the innate immunity lymphocytes responsible for fighting against virus-infected and cancerous cells. They have various mechanisms to suppress viral infections. On the other hand, viruses have evolved to utilize different ways to evade NK cell-mediated responses. Viruses can balance the response by regulating the cytokine release pattern and changing the proportion of activating and inhibitory receptors on the surface of NK cells. Exosomes are a subtype of extracellular vesicles that are involved in intercellular communication. Most cell populations can release these nano-sized vesicles, and it was shown that these vesicles produce identical outcomes to the originating cell from which they are released. In recent years, the role of NK cell-derived exosomes in various diseases including viral infections has been highlighted, drawing attention to utilizing the therapeutic potential of these nanoparticles. In this article, the role of NK cells in various viral infections and the mechanisms used by viruses to evade these important immune system cells are initially examined. Subsequently, the role of NK cell exosomes in controlling various viral infections is discussed. Finally, the current position of these cells in the treatment of viral infections and the therapeutic potential of their exosomes are reviewed. 4PXMbRdccbJJLWkDCVJhsa Video Abstract [ABSTRACT FROM AUTHOR]

Background: Cancers aggressively reorganize collagen in their microenvironment, leading to the evasion of tumor cells from immune surveillance. However, the biological significance and molecular mechanism of collagen alignment in breast cancer (BC) have not been well established. Methods: In this study, BC-related RNA-Seq data were obtained from the TCGA database to analyze the correlation between DDR1 and immune cells. Mouse BC cells EO771 were selected for in vitro validation, and dual-luciferase experiments were conducted to examine the effect of TFAP2A on DDR1 promoter transcription activity. ChIP experiments were performed to assess TFAP2A enrichment on the DDR1 promoter, while Me-RIP experiments were conducted to detect TFAP2A mRNA m6A modification levels, and PAR-CLIP experiments were conducted to determine VIRMA's binding to TFAP2A mRNA and RIP experiments to investigate HNRNPC's recognition of m6A modification on TFAP2A mRNA. Additionally, an in vivo mouse BC transplant model and the micro-physiological system was constructed for validation, and Masson staining was used to assess collagen fiber arrangement. Immunohistochemistry was conducted to identify the number of CD8-positive cells in mouse BC tumors and Collagen IV content in ECM, while CD8 + T cell migration experiments were performed to measure CD8 + T cell migration. Results: Bioinformatics analysis showed that DDR1 was highly expressed in BC and negatively correlated with the proportion of anti-tumor immune cell infiltration. In vitro cell experiments indicated that VIRMA, HNRNPC, TFAP2A, and DDR1 were highly expressed in BC cells. In addition, HNRNPC promoted TFAP2A expression and, therefore, DDR1 transcription by recognizing the m6A modification of TFAP2A mRNA by VIRMA. In vivo animal experiments further confirmed that VIRMA and HNRNPC enhanced the TFAP2A/DDR1 axis, promoting collagen fiber alignment, reducing anti-tumor immune cell infiltration, and promoting immune escape in BC. Conclusion: This study demonstrated that HNRNPC promoted DDR1 transcription by recognizing VIRMA-unveiled m6A modification of TFAP2A mRNA, which enhanced collagen fiber alignment and ultimately resulted in the reduction of anti-tumor immune cell infiltration and promotion of immune escape in BC. [ABSTRACT FROM AUTHOR]

Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of immune checkpoint blockade. Understanding the origin of TAMCs was found to be the essential to determining their functional heterogeneity and, developing cancer immunotherapy strategies. While myeloid-biased differentiation in the bone marrow has been traditionally considered as the primary source of TAMCs, the abnormal differentiation of splenic hematopoietic stem and progenitor cells, erythroid progenitor cells, and B precursor cells in the spleen, as well as embryo-derived TAMCs, have been depicted as important origins of TAMCs. This review article provides an overview of the literature with a focus on the recent research progress evaluating the heterogeneity of TAMCs origins. Moreover, this review summarizes the major therapeutic strategies targeting TAMCs with heterogeneous sources, shedding light on their implications for cancer antitumor immunotherapies. [ABSTRACT FROM AUTHOR]

Since invasion, there will be a tug-of-war between host and virus to scramble cellular resources, for either restraining or facilitating infection. Alternative splicing (AS) is a conserved and critical mechanism of processing pre-mRNA into mRNAs to increase protein diversity in eukaryotes. Notably, this kind of post-transcriptional regulatory mechanism has gained appreciation since it is widely involved in virus infection. Here, we highlight the important roles of AS in regulating viral protein expression and how virus in turn hijacks AS to antagonize host immune response. This review will widen the understandings of host-virus interactions, be meaningful to innovatively elucidate viral pathogenesis, and provide novel targets for developing antiviral drugs in the future. [ABSTRACT FROM AUTHOR]

Background: Bronchial premalignant lesions (PMLs) are composed primarily of cells resembling basal epithelial cells of the airways, which through poorly understood mechanisms have the potential to progress to lung squamous cell carcinoma (LUSC). Despite ongoing efforts that have mapped gene expression and cell diversity across bronchial PML pathologies, signaling and transcriptional events driving malignancy are poorly understood. Evidence has suggested key roles for the Hippo pathway effectors YAP and TAZ and associated TEAD and TP63 transcription factor families in bronchial basal cell biology and LUSC. In this study we examine the functional association of YAP/TAZ, TEADs and TP63 in bronchial epithelial cells and PMLs. Methods: We performed RNA-seq in primary human bronchial epithelial cells following small interfering RNA (siRNA)-mediated depletion of YAP/TAZ, TEADs or TP63, and combined these data with ChIP-seq analysis of these factors. Directly activated or repressed genes were identified and overlapping genes were profiled across gene expression data obtained from progressive or regressive human PMLs and across lung single cell RNA-seq data sets. Results: Analysis of genes regulated by YAP/TAZ, TEADs, and TP63 in human bronchial epithelial cells revealed a converged transcriptional network that is strongly associated with the pathological progression of bronchial PMLs. Our observations suggest that YAP/TAZ-TEAD-TP63 associate to cooperatively promote basal epithelial cell proliferation and repress signals associated with interferon responses and immune cell communication. Directly repressed targets we identified include the MHC Class II transactivator CIITA, which is repressed in progressive PMLs and associates with adaptive immune responses in the lung. Our findings provide molecular insight into the control of gene expression events driving PML progression, including those contributing to immune evasion, offering potential new avenues for lung cancer interception. Conclusions: Our study identifies important gene regulatory functions for YAP/TAZ-TEAD-TP63 in the early stages of lung cancer development, which notably includes immune-suppressive roles, and suggest that an assessment of the activity of this transcriptional complex may offer a means to identify immune evasive bronchial PMLs and serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

The immunoreceptor NKG2D, which is expressed on NK cells and T cell subsets is critically involved in tumor immune surveillance. This applies in particular to acute myeloid leukemia (AML), which evades immune detection by downregulation of NKG2D ligands (NKG2D-L), including MICA. The absence of NKG2D-L on AML cells is moreover associated with leukemia stem cell characteristics. The NKG2D/NKG2D-L system thus qualifies as an interesting and promising therapeutic target. Here we aimed to identify transcription factors susceptible to pharmacological stimulation resulting in the expression of the NKG2D-L MICA in AML cells to restore anti-tumor activity. Using a CRISPR-based engineered ChIP (enChIP) assay for the MICA promoter region and readout by mass spectrometry-based proteomics, we identified the transcription factor krüppel-like factor 4 (KLF4) as associated with the promoter. We demonstrated that the MICA promoter comprises functional binding sites for KLF4 and genetic as well as pharmacological gain- and loss-of-function experiments revealed inducible MICA expression to be mediated by KLF4. Furthermore, induction in AML cells was achieved with the small compound APTO253, a KLF4 activator, which also inhibits MYC expression and causes DNA damage. This induction in turn yielded increased expression and cell surface presentation of MICA, thus rendering AML cells more susceptible to NK cell-mediated killing. These data unravel a novel link between APTO253 and the innate anti-tumor immune response providing a rationale for targeting AML cells via APTO253-dependent KFL4/MICA induction to allow elimination by endogenous or transplanted NK and T cells in vivo. D1rDmzAPriWUyYABRWPo9P Video Abstract [ABSTRACT FROM AUTHOR]

Background: Despite successful control efforts in China over the past 60 years, zoonotic schistosomiasis caused by Schistosoma japonicum remains a threat with transmission ongoing and the risk of localised resurgences prompting calls for a novel integrated control strategy, with an anti-schistosome vaccine as a core element. Anti-schistosome vaccine development and immunisation attempts in non-human mammalian host species, intended to interrupt transmission, and utilising various antigen targets, have yielded mixed success, with some studies highlighting variation in schistosome antigen coding genes (ACGs) as possible confounders of vaccine efficacy. Thus, robust selection of target ACGs, including assessment of their genetic diversity and antigenic variability, is paramount. Tetraspanins (TSPs), a family of tegument-surface antigens in schistosomes, interact directly with the host's immune system and are promising vaccine candidates. Here, for the first time to our knowledge, diversity in S. japonicum TSPs (SjTSPs) and the impact of diversifying selection and sequence variation on immunogenicity in these protiens were evaluated. Methods: SjTSP sequences, representing parasite populations from seven provinces across China, were gathered by baiting published short-read NGS data and were analysed using in silico methods to measure sequence variation and selection pressures and predict the impact of selection on variation in antigen protein structure, function and antigenic propensity. Results: Here, 27 SjTSPs were identified across three subfamilies, highlighting the diversity of TSPs in S. japonicum. Considerable variation was demonstrated for several SjTSPs between geographical regions/provinces, revealing that episodic, diversifying positive selection pressures promote amino acid variation/variability in the large extracellular loop (LEL) domain of certain SjTSPs. Accumulating polymorphisms in the LEL domain of SjTSP-2, -8 and -23 led to altered structural, functional and antibody binding characteristics, which are predicted to impact antibody recognition and possibly blunt the host's ability to respond to infection. Such changes, therefore, appear to represent a mechanism utilised by S. japonicum to evade the host's immune system. Conclusion: Whilst the genetic and antigenic geographic variability observed amongst certain SjTSPs could present challenges to vaccine development, here we demonstrate conservation amongst SjTSP-1, -13 and -14, revealing their likely improved utility as efficacious vaccine candidates. Importantly, our data highlight that robust evaluation of vaccine target variability in natural parasite populations should be a prerequisite for anti-schistosome vaccine development. [ABSTRACT FROM AUTHOR]

Background: The high immune evasion ability of SARS-COV-2 Omicron variant surprised the world and appears to be far stronger than any previous variant. Previous to Omicron it has been difficult to assess and compare immune evasion ability of different variants, including the Beta and Delta variants, because of the relatively small numbers of reinfections and because of the problems in correctly identifying reinfections in the population. This has led to different claims appearing in the literature. Thus we find claims of both high and low immune evasion for the Beta variant. Some findings have suggested that the Beta variant has a higher immune evasion ability than the Delta variant in South Africa, and others that it has a lower ability. Method: In this brief report, we re-analyse a unique dataset of variant-specific reinfection data and a simple model to correct for the infection attack rates of different variants. Result: We find that a model with the Delta variant having an equal or higher immune evasion ability than Beta variant is compatible with the data. Conclusion: We conclude that the immune evasion ability of Beta variant is not stronger than Delta variant, and indeed, the immune evasion abilities of both variants are weak in South Africa. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by m6A writers, erasers, and readers, m6A modulation is involved in myriad physiological and pathological processes. Extensive studies have demonstrated m6A modulation in diverse tumours, with effects on tumorigenesis, metastasis, and resistance. Recent evidence has revealed an emerging role of m6A modulation in tumour immunoregulation, and divergent m6A methylation patterns have been revealed in the tumour microenvironment. To depict the regulatory role of m6A methylation in the tumour immune microenvironment (TIME) and its effect on immune evasion, this review focuses on the TIME, which is characterized by hypoxia, metabolic reprogramming, acidity, and immunosuppression, and outlines the m6A-regulated TIME and immune evasion under divergent stimuli. Furthermore, m6A modulation patterns in anti-tumour immune cells are summarized. [ABSTRACT FROM AUTHOR]

Duck hepatitis A virus type 1 (DHAV-1) is an acute, highly lethal infectious agent that infects ducklings and causes up to 95% mortality in ducklings up to 1 week of age, posing a significant economic threat to the duck farming industry. Previous studies have found that the proteolytic enzyme 3 C encoded by DHAV-1 can inhibit the IRF7 protein from blocking the upstream signaling pathway of the type I interferon to promote viral replication. However, there are still few studies on the mechanism of DHAV-1 in immune evasion. Here, we demonstrate that the DHAV-1 3CD protein can interact with IRF7 protein and reduce IRF7 protein expression without directly affecting IRF7 protein nuclear translocation. Further studies showed that the 3CD protein could reduce the expression of RIG-I protein without affecting its transcription level. Furthermore, we found that the 3CD protein interacted with the N-terminal structural domain of RIG-I protein, interfered with the interaction between RIG-I and MAVS, and degraded RIG-I protein through the proteasomal degradation pathway, thereby inhibiting its mediated antiviral innate immunity to promote DHAV-1 replication. These data suggest a novel immune evasion mechanism of DHAV-1 mediated by the 3CD protein, and the results of this experiment are expected to improve the understanding of the biological functions of the viral precursor protein and provide scientific data to elucidate the mechanism of DHAV-1 infection and pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Recently genome-based studies revealed that the abnormality of Hippo signaling is pervasive in TNBC and played important role in cancer progression. RING finger protein 31 (RNF31) comes to RING family E3 ubiquitin ligase. Our previously published studies have revealed RNF31 is elevated in ER positive breast cancer via activating estrogen signaling and suppressing P53 pathway. Methods: We used several TNBC cell lines and xenograft models and performed immuno-blots, QPCR, in vivo studies to investigate the function of RNF31 in TNBC progression. Result: Here, we demonstrate that RNF31 plays tumor suppressive function in triple negative breast cancer (TNBC). RNF31 depletion increased TNBC cell proliferation and migration in vitro and in vitro. RNF31 depletion in TNBC coupled with global genomic expression profiling indicated Hippo signaling could be the potential target for RNF31 to exert its function. Further data showed that RNF31 depletion could increase the level of YAP protein, and Hippo signaling target genes expression in several TNBC cell lines, while clinical data illustrated that RNF31 expression correlated with longer relapse-free survival in TNBC patients and reversely correlated with YAP protein level. The molecular biology assays implicated that RNF31 could associate with YAP protein, facilitate YAP poly-ubiquitination and degradation at YAP K76 sites. Interestingly, RNF31 could also repress PDL1 expression and sensitive TNBC immunotherapy via inhibiting Hippo/YAP/PDL1 axis. Conclusions: Our study revealed the multi-faced function of RNF31 in different subtypes of breast malignancies, while activation RNF31 could be a plausible strategy for TNBC therapeutics.Highlights: 1. RNF31 restrains cancer cell progression in TNBC. 2. RNF31 regulates YAP protein stability via promoting YAP K48-linked poly-ubiquitination. 3. RNF31 represses immune evasion via suppressing YAP/PD-L1 axis in TNBC. [ABSTRACT FROM AUTHOR]

Cancer development is an evolutionary process. A key selection pressure is exerted by therapy, one of the few players in cancer evolution that can be controlled. As such, an understanding of how treatment acts to sculpt the tumour and its microenvironment and how this influences a tumour's subsequent evolutionary trajectory is critical. In this review, we examine cancer evolution and intra-tumour heterogeneity in the context of therapy. We focus on how radiotherapy, chemotherapy and immunotherapy shape both tumour development and the environment in which tumours evolve and how resistance can develop or be selected for during treatment. [ABSTRACT FROM AUTHOR]

Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 virus has been raging globally for over 2 years with no end in sight. It has become clear that this virus possesses enormous genetic plasticity, and it will not be eradicated. Under increasing selective pressure from population immunity, the evolution of SARS-CoV-2 has driven it towards greater infectivity, and evasion of humoral and cellular immunity. Omicron and its expanding army of subvariants and recombinants have impaired vaccine protection and made most antibody drugs obsolete. Antiviral drugs, though presently effective, may select for more resistant strains over time. It may be inevitable, then, that future SARS-CoV-2 variants will be immune to our current virus-directed countermeasures. Thus, to gain control over the virus, we need to adopt a new paradigm in searching for next-generation countermeasures and develop host-directed therapeutics (HDTx) and host-directed antivirals (HDA). Different from the virus-directed countermeasures, HDTx and HDA may offer variant agnostic treatment to reduce the risk and severity of infections. In addition, they may exert more uniform effects against the genetically diverse SARS-CoV-2 quasispecies, thereby diminishing the risk of selecting resistant variants. Some promising HDTx and HDA approaches are summarized here. [ABSTRACT FROM AUTHOR]

Background: To investigate the mechanism of Golgi matrix protein 130(GM130) regulating the antiviral immune response of TLR3 after herpes simplex virus type 1(HSV-1) infection of microglia cells. We explored the regulatory effects of berberine on the immune response mediated by GM130 and TLR3., Methods: An in vitro model of HSV-1 infection was established by infecting BV2 cells with HSV-1., Results: Compared to the uninfected group, the Golgi apparatus (GA) fragmentation and GM130 decreased after HSV-1 infection; TLR3 increased at 6 h and began to decrease at 12 h after HSV-1 infection; the secretion of interferon-beta(IFN-β), tumour necrosis factor alpha(TNF-α), and interleukin-6(IL-6) increased after infection. Knockdown of GM130 aggravated fragmentation of the GA and caused TLR3 to further decrease, and the virus titer also increased significantly. GM130 knockdown inhibits the increase in TLR3 and inflammatory factors induced by TLR3 agonists and increases the viral titer. Overexpression of GM130 alleviated fragmentation of the GA induced by HSV-1, partially restored the levels of TLR3, and reduced viral titers. GM130 overexpression reversed the reduction in TLR3 and inflammatory cytokine levels induced by TLR3 inhibitors. Therefore, the decrease in GM130 levels caused by HSV-1 infection leads to increased viral replication by inhibiting TLR3-mediated innate immunity. Berberine can protect the GA and reverse the downregulation of GM130, as well as the downregulation of TLR3 and its downstream factors after HSV-1 infection, reducing the virus titer., Conclusions: In microglia, one mechanism of HSV-1 immune escape is disruption of the GM130/TLR3 pathway. Berberine protects the GA and enhances TLR3-mediated antiviral immune responses., (© 2024. The Author(s).)

Background: Genomic studies of colorectal cancer have revealed the complex genomic heterogeneity of the tumor. The acquisition and selection of genomic alterations may be critical to understanding the initiation and progression of this disease.Methods: In this study, we have systematically characterized the clonal architecture of 97 driver genes in 536 colorectal cancer patients from TCGA.Results: A high proportion of clonal mutations in 93 driver genes were observed. 40 genes showed significant associations between their clonality and multiple clinicopathologic factors. Kaplan-Meier analysis suggested that the mutation clonality of ANK1, CASP8, SMAD2, and ARID1A had a significant impact on the CRC patients' outcomes. Multivariable analysis revealed that subclonal ANK1 mutations, clonal CASP8 mutations, and clonal SMAD2 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. The poor outcome of the subclonal ANK1 mutation may be caused by upregulation of IL4I1, IDO1, IFNG and MAPK12 which showed potential roles in tumor immune evasion through accumulation of immunosuppressive cells such as regulatory T cells and myeloid derived suppressor cells.Conclusion: These results suggested that the clonality of driver genes could act as prognostic markers and potential therapeutic targets in human colorectal cancer. [ABSTRACT FROM AUTHOR]

The emergence of the novel GII.17 Kawasaki 2014 norovirus variant raising the interest of the public, has replaced GII.4 as the predominant cause of noroviruses outbreaks in East Asia during 2014–2015. Antigenic variation of the capsid protein is considered as one of the key mechanisms of norovirus evolution. In this study, we screened a panel of GII.17 mutants. First, we produced norovirus P proteins using cell-free protein synthesis (CFPS) system, comparing the results to pure proteins expressed in a cell-based system. Next, we determined the binding capability of specific monoclonal antibody (mAb) 2D11 using a unique set of wild-type GII.17 strains. Results of the EIA involving a panel of mutant cell-free proteins indicated that Q298 was the key residue within loop 1. These data highlighted the essential residues in the linear antibody binding characteristics of novel GII.17. Furthermore, it supported the CFPS as a promising tool for rapidly screening mutants via the scalable expression of norovirus P proteins. [ABSTRACT FROM AUTHOR]

Background: One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterogenous and progressive natures. Genetic and epigenetic changes play significant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation. Aim of review: The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined. Key scientific concepts of review: The aberrant expression of lncRNAs in prostate cancer has been well-documented and progression rate of tumor cells are regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarker. [ABSTRACT FROM AUTHOR]

Background: The two oncogenic human gammaherpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), both downregulate immune surface molecules, such as MHC-I, ICAM-1, and B7-2, enabling them to evade T-cell and natural killer cell immunity. Both also either encode for human cyclin homologues or promote cellular cyclin activity, and this has been shown to be important for proliferation and survival of gammaherpesvirus-induced tumors. CDK4/6 inhibitors, which are approved for certain breast cancers, have been shown to enhance expression of MHC-I in cell lines and murine models of breast cancer, and this was attributed to activation of interferons by endogenous retrovirus elements. However, it was not known if this would occur in gammaherpesvirus-induced tumors in which interferons are already activated.Methods: Multiple KSHV/EBV-infected cell lines were treated with CDK4/6 inhibitors. The growth of viable cells and expression of surface markers was assessed. T cell activation stimulated by the treated cells was assayed by a T-cell activation bioassay. Both viral and host gene expression was surveyed using RT-qPCR.Results: Three CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib, inhibited cell growth in KSHV-induced primary effusion lymphoma (PEL) and EBV positive Burkitt's lymphoma (BL) cell lines, and KSHV-infected human umbilical vein endothelial cells (HUVECs). Moreover, CDK4/6 inhibitors increased mRNA and surface expression of MHC-I in all three and prevented downregulation of MHC-I surface expression during lytic replication in KSHV-infected cells. CDK4/6 inhibitors also variably increased mRNA and surface expression of ICAM-1 and B7-2 in the tested lines. Abemaciclib also significantly enhanced T-cell activation induced by treated PEL and BL cells. Certain gammaherpesvirus genes as well as endogenous retrovirus (ERV) 3-1 genes were enhanced by CDK4/6 inhibitors in most PEL and BL lines and this enhancement was associated with expression of gamma interferon-induced genes including MHC-I.Conclusions: These observations provide evidence that CDK4/6 inhibitors can induce expression of surface immune markers MHC-I, B7-2, and ICAM-1 in gammaherpesvirus-infected cell lines and induce virus-specific immunity. They can thus thwart virus-induced immune evasion. These effects, along with their direct effects on KSHV- or EBV-induced tumors, provide a rational for the clinical testing of these drugs in these tumors. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer. Methods: A circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays. Results: circDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy. Conclusions: Overall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression. [ABSTRACT FROM AUTHOR]

Background: Patients with lung adenocarcinoma (LUAD) have a low response rate to immune checkpoint blockade. It is highly important to explore the tumor immune escape mechanism of LUAD patients and expand the population of patients who may benefit from immunotherapy., Methods: Based on 954 bulk RNA-seq data of LUAD patients and 15 single-cell RNA-seq data, the relationships between tumor immune dysfunction and exclusion (TIDE) scores and survival prognosis in each patient were calculated and evaluated, and the immune escape mechanism affecting the independent prognosis of LUAD patients was identified. Functional enrichment analysis explored the antitumour immune response and biological behavior of tumor cells among different LUAD groups. Single-cell annotation and pseudotemporal analysis were used to explore the target molecules and immune escape mechanisms of LUAD., Results: Myeloid-derived suppressor cells (MDSCs) and IRF8 were identified as risk and protective factors for the independent prognosis of LUAD patients, respectively. In the tumor microenvironment of patients with high infiltration of MDSCs, the antitumor immune response is significantly suppressed, while tumor cell division, proliferation, and distant metastasis are significantly enhanced. Single-cell RNA-seq analysis revealed that IRF8 is an important regulator of MDSC differentiation in LUAD myeloid cells. In addition, IRF8 may regulate the differentiation of MDSCs through the IL6-JAK-STAT3 signalling pathway., Conclusions: IRF8 deficiency impairs the normal development of LUAD myeloid cells and induces their differentiation into MDSCs, thereby accelerating the immune escape of LUAD cells. IRF8-targeted activation to inhibit the formation of MDSCs may be a new target for immunotherapy in LUAD., (© 2024. The Author(s).)