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Abstract Tertiary lymphoid structures are immune cell aggregates linked with cancer outcomes, but their interactions with tumour cell aggregates are unclear. Using nasopharyngeal carcinoma as a model, here we analyse single-cell transcriptomes of 343,829 cells from 77 biopsy and blood samples and spatially-resolved transcriptomes of 31,316 spots from 15 tumours to decipher their components and interactions with tumour cell aggregates. We identify essential cell populations in tertiary lymphoid structure, including CXCL13+ cancer-associated fibroblasts, stem-like CXCL13+CD8+ T cells, and B and T follicular helper cells. Our study shows that germinal centre reaction matures plasma cells. These plasma cells intersperse with tumour cell aggregates, promoting apoptosis of EBV-related malignant cells and enhancing immunotherapy response. CXCL13+ cancer-associated fibroblasts promote B cell adhesion and antibody production, activating CXCL13+CD8+ T cells that become exhausted in tumour cell aggregates. Tertiary lymphoid structure-related cell signatures correlate with prognosis and PD-1 blockade response, offering insights for therapeutic strategies in cancers.

Abstract The response to programmed death-1 (PD-1) blockade varies in hepatocellular carcinoma (HCC). We utilize a panel of 16 serum factors to show that a circulating level of serum amyloid A (SAA) > 20.0 mg/L has the highest accuracy in predicting anti-PD-1 resistance in HCC. Further experiments show a correlation between peritumoral SAA expression and circulating SAA levels in patients with progressive disease after PD-1 inhibition. In vitro experiments demonstrate that SAA induces neutrophils to express PD-L1 through glycolytic activation via an LDHA/STAT3 pathway and to release oncostatin M, thereby attenuating cytotoxic T cell function. In vivo, genetic or pharmacological inhibition of STAT3 or SAA eliminates neutrophil-mediated immunosuppression and enhances antitumor efficacy of anti-PD-1 treatment. This study indicates that SAA may be a critical inflammatory cytokine implicated in anti-PD-1 resistance in HCC. Targeting SAA-induced PD-L1+ neutrophils through STAT3 or SAA inhibition may present a potential approach for overcoming anti-PD1 resistance.

ABSTRACTThe research and development of messenger RNA (mRNA) cancer vaccines have gradually overcome numerous challenges through the application of personalized cancer antigens, structural optimization of mRNA, and the development of alternative RNA-based vectors and efficient targeted delivery vectors. Clinical trials are currently underway for various cancer vaccines that encode tumor-associated antigens (TAAs), tumor-specific antigens (TSAs), or immunomodulators. In this paper, we summarize the optimization of mRNA and the emergence of RNA-based expression vectors in cancer vaccines. We begin by reviewing the advancement and utilization of state-of-the-art targeted lipid nanoparticles (LNPs), followed by presenting the primary classifications and clinical applications of mRNA cancer vaccines. Collectively, mRNA vaccines are emerging as a central focus in cancer immunotherapy, offering the potential to address multiple challenges in cancer treatment, either as standalone therapies or in combination with current cancer treatments.

Abstract Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation‐induced double‐stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation‐induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS‐STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC‐derived RECQL4 disrupts cGAS‐STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC.

Summary: The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

Abstract The remarkable success of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has propelled the rapid development of this vaccination technology in recent years. Over the last three decades, numerous studies have shown the considerable potential of mRNA vaccines that elicit protective immune responses against pathogens or cancers in preclinical studies or clinical trials. These effective mRNA vaccines usually contain specific adjuvants to obtain the desired immune effect. Vaccine adjuvants traditionally are immunopotentiators that bind to pattern recognition receptors (PRRs) of innate immune cells to increase the magnitude or achieve qualitative alteration of immune responses, finally enhancing the efficacy of vaccines. Generally, adjuvants are necessary parts of competent vaccines. According to the existing literature, adjuvants in mRNA vaccines can be broadly classified into three categories: 1) RNA with self-adjuvant characteristics, 2) components of the delivery system, and 3) exogenous immunostimulants. This review summarizes the three types of adjuvants used in mRNA vaccines and provides a comprehensive understanding of molecular mechanisms by which adjuvants exert their functions in mRNA vaccines.

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Extracting relation quintuple and feature words from unstructured text is a prelude to the construction of the scientific knowledge base. At present, the prior works use explicit clues between entities to study this task but ignore the use and the association of the feature words. In this work, we propose a new method to generate self-adaptive feature words from the original text for every single sample. These words can add additional correlation information to the knowledge graph. We allow the model to generate a new word representation and apply it to the original sentence to judge the relation type and locate the head and tail of the relation quintuple. Compared with the previous works, the feature words increase the flexibility of relying on information and improve the explanatory ability. Extensive experiments on scientific field datasets illustrate that the self-adaptive feature words method (SAFW) is good at ferreting out the unique feature words and obtaining the core part for the quintuple. It achieves good performance on four public datasets and obtains a markable performance improvement compared with other baselines.

Most cases of hepatocellular carcinoma (HCC) are able to be diagnosed through regular surveillance in an identifiable patient population with chronic hepatitis B or cirrhosis. Nevertheless, 50% of global cases might present incidentally owing to symptomatic advanced-stage HCC after worsening of liver dysfunction. A systematic search based on PUBMED was performed to identify relevant outcomes, covering newer surveillance modalities including secretory proteins, DNA methylation, miRNAs, and genome sequencing analysis which proposed molecular expression signatures as ideal tools in the early-stage HCC detection. In the face of low accuracy without harmonization on the analytical approaches and data interpretation for liquid biopsy, a more accurate incidence of HCC will be unveiled by using deep machine learning system and multiplex immunohistochemistry analysis. A combination of molecular-secretory biomarkers, high-definition imaging and bedside clinical indexes in a surveillance setting offers a comprehensive range of HCC potential indicators. In addition, the sequential use of numerous lines of systemic anti-HCC therapies will simultaneously benefit more patients in survival. This review provides an overview on the most recent developments in HCC theranostic platform.

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Synthetic mRNAs are rising rapidly as alternative therapeutic agents for delivery of proteins. However, the practical use of synthetic mRNAs has been restricted by their low cellular stability as well as poor protein production efficiency. The key roles of poly(A) tail on mRNA biology inspire us to explore the optimization of tail sequence to overcome the aforementioned limitations. Here, the systematic substitution of non-A nucleotides in the tails revealed that cytidine-containing tails can substantially enhance the protein production rate and duration of synthetic mRNAs both in vitro and in vivo. Such C-containing tails shield synthetic mRNAs from deadenylase CCR4-NOT transcription complex, as the catalytic CNOT proteins, especially CNOT6L and CNOT7, have lower efficiency in trimming of cytidine. Consistently, these enhancement effects of C-containing tails were observed on all synthetic mRNAs tested and were independent of transfection reagents and cell types. As the C-containing tails can be used along with other mRNA enhancement technologies to synergically boost protein production, we believe that these tails can be broadly used on synthetic mRNAs to directly promote their clinical applications.

Introduction: Immunochemotherapy using PD-1/PD-L1 antibodies in combination with chemotherapeutic agents has become a mainstream treatment for cancer patients, but it remains unclear which drug combinations would produce best therapeutic outcome. Objectives: The purpose of this study was to investigate two common chemotherapeutic drugs, gemcitabine and cisplatin, for their impacts on the therapeutic efficacy of PD-1 antibody in K-ras-driven cancers known to overexpress PD-L1. Methods: Both in vitro assays and syngeneic mouse tumor models were used in this study. Biochemical and molecular assays were used to determine the effects of drugs on T cell functions in cell culture models and in mouse/human tumor tissues. Allograft tumor models with K-ras mutation were used to investigate the combination effect of gemcitabine or cisplatin with immunotherapy. Data of lung cancer patients with K-ras mutation treated with cisplatin and toripalimab were analyzed to evaluate the clinical relevance of the lab findings. Results: Cisplatin and gemcitabine unexpectedly exert opposite effect on the therapeutic activity of PD-1 antibody in vivo. Gemcitabine antagonizes the therapeutic effect of PD-1 antibody due to its significant inhibition on CD8+ T cell infiltration, which was observed both in mouse tumor allografts and in human pancreatic cancer tissues. In contrast, cisplatin shows synergistic activity with PD-1 antibody by activation of CD8+ T cells through the DNA damage-mediated cGAS-STING sensing mechanism, leading to increase of T cell infiltration and secretion of antitumor cytokines. Clinical data show that a combination of cisplatin with PD-1 antibody toripalimab could be effective in advanced lung cancer patients with K-ras mutation who failed prior therapies. Conclusions: Our study shows that a key factor in selecting chemotherapeutic agents for immunochemotherapy is the drug’s impact on T cell functions, and that cisplatin-based chemotherapy is an excellent choice for combination with immune checkpoint antibody to achieve favorable clinical outcome.

Abstract Host organisms use different innate immune mechanisms to defend against pathogenic infections, while tight control of innate immunity is essential for proper immune induction and balance. Here, we reported that apoptotic induction or caspase-3 overexpression caused dramatic reduction of differently triggered cytokine signalings in human cells, murine primary cells and mouse model, while the loss of caspase-3 or inhibiting apoptosis markedly enhances these immune signalings. Furthermore, caspase-3 can mediate the cleavage of NF-κB members p65/RelA, RelB, and c-Rel via its protease activity. And the caspase-3-resistant p65/RelA, RelB, or c-Rel mutant mostly restored the caspase-3-induced suppression of cytokine production. Interestingly, we further uncovered that apoptotic induction also dramatically inhibited Toll immune signaling in Drosophila, and the Drosophila effector caspases, drICE and DCP-1, also mediated the degradation of DIF, the NF-κB of Toll signaling. Together, our findings demonstrate apoptotic effector caspases, including mammalian caspase-3 and fly drICE/DCP-1, can function as repressors of NF-κB-mediated innate immune signalings.

Given motorized spindles’ extensive periods of prolonged high-velocity operation, they are prone to temperature changes, which leads to the problem of thermal error, leading to diminished precision in machining operations. To address the thermal error issue in motorized spindles of computer numerical control (CNC) machine tools, this study proposes a pelican optimization algorithm (POA)-optimized convolutional neural network (CNN)–long short-term memory (LSTM) hybrid neural network model (POA-CNN-LSTMNN). Initially, the identification of temperature-sensitive locations in the spindle system is performed using a combination of hierarchical clustering, the K-medoids algorithm, and Pearson’s coefficient calculation. Subsequently, the temperature data from these identified points, along with real-time collected spindle thermal error data, are employed to construct the model. The Pelican optimization algorithm is used to enhance the model parameters to achieve the best performance. Finally, the proposed model is subjected to a comparative analysis with other thermal error prediction models. Drawing from the experimental findings, it is evident that the POA-CNN-LSTMNN model exhibits superior prediction performance.

Prevalent copy number alteration is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immune response in OV. Through interrogating the RAD21-regulated transcriptional program, we found that RAD21 directly interacts with YAP/TEAD4 transcriptional corepressors and recruits the NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti–PD-1 efficacy with increased intratumoral CD8+ T cell effector activity. Our study identifies a RAD21–YAP/TEAD4–NuRD corepressor complex in immune modulation, and thus provides a potential target and biomarker for precision immunotherapy in OV.

Messenger RNA (mRNA)-based cancer vaccine has become a popular approach for developing personalized and effective antitumor immunotherapy. To achieve robust antitumor efficacy, mRNA-encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells for efficient antigen presentation; meanwhile, the vaccine would have adjuvant effect by stimulating innate immune response to boost the full activation of adaptive immunity. Recently, we reported a minimalist nanovaccine by formulating tumor antigen-encoding mRNA with a lipid-like material named C1, which could efficiently deliver mRNA into dendritic cells with simultaneous Toll-like receptor 4 (TLR4) stimulation, together induced T cell activation. Importantly, C1 mRNA nanovaccine exhibited significant antitumor efficacy on several tumor mouse models. Here, we discuss the nanovector-facilitated mRNA delivery and translation in dendritic cells, the self-adjuvant property of nanovectors, the challenges of personalized tumor antigen selection, and the potential strategies for developing efficacious mRNA cancer vaccines targeting the immunosuppressive tumor microenvironment.

Background Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments.Methods Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture.Results Increased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR−/− mice but not TKO or IRF3−/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion.Conclusions These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.

ObjectivesTyrosine kinase inhibitors (TKIs) are a standard care option in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI-based combination treatment modes show encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on overall survival (OS).Materials and methodsRandomized controlled trials and meeting abstracts that investigated EGFR-TKIs alone or in combination as front-line care for patients with NSCLC were systematically searched in relevant databases and reviewed. Fixed and random effects network meta-analysis models were used to estimate progression-free survival (PFS), OS, overall response rate, and grade three and higher adverse events (AEs). Surface under the cumulative ranking curves (SUCRAs) were used to rank treatment effects.ResultsEighteen studies covering six treatments and involving a total of 4389 patients were included in this network meta-analysis. On OS, the top three treatment were first-generation EGFR-TKIs (1G EGFR-TKIs) plus chemotherapy (SUCRA, 88.1%), osimertinib (SUCRA, 65.8%) and second-generation EGFR-TKIs (2GEGFR-TKIs) (SUCRA, 63.3%). On PFS, the top three treatments were osimertinib (SUCRA, 96.0%), 1G EGFR-TKIs plus chemotherapy (SUCRA, 67.1%), and 1G EGFR-TKIs plus antiangiogenesis (SUCRA, 48.2%). Two types of TKI-based combination therapy have significantly higher risk of grade three and higher AEs than TKI alone.Conclusion1G EGFR-TKIs plus chemotherapy and osimertinib seem to be the two better options as first-line care in advanced NSCLC patients with EGFR-mutation. Osimertinib caused the lowest incidence of AEs. However, TKIs-based combination therapy significantly increased AEs.

Nasopharyngeal carcinoma is a diverse cancer characterised by a heterogeneous microenvironment. Here, the authors use single cell sequencing to analyse the tumour microenvironment in 10 nasopharyngeal carcinoma tumours and identify different cell types including immune-suppressive T regulatory, tolerogenic dendritic, and exhausted CD8 T cells.

To better solve the problem of thermal error of computerized numerical control machining equipment (CNCME), a thermal error prediction model based on the sparrow search algorithm and long short-term memory neural network (SSA-LSTMNN) is proposed. Firstly, the Fuzzy C-means clustering algorithm (FCMCA) is used to screen the key temperature-sensitive points of the CNCME. Secondly, by taking the temperature rise data of key temperature-sensitive points as input and the corresponding time thermal error data as output, we established the SSA-LSTMNN thermal error prediction model. The SSA is used to optimize the parameters of LSTMNN and make its performance play the best. Taking the VMC1060 vertical machining center as the research object, we carried out the experiment. Finally, the prediction effect of the proposed model is compared with the article swarm optimized algorithm and LSTM neural network (PSOA-LSTMNN), the LSTMNN, and the traditional recurrent neural network (TRNN) model. The results show that the average values of the predicted residual fluctuations of the SSA-LSTMNN model are all more than 44% lower than those of the other three models under different operating conditions, which has a strong practicality.

Abstract Background As core units of organ tissues, cells of various types play their harmonious rhythms to maintain the homeostasis of the human body. It is essential to identify the characteristics of cells in human organs and their regulatory networks for understanding the biological mechanisms related to health and disease. However, a systematic and comprehensive single-cell transcriptional profile across multiple organs of a normal human adult is missing. Results We perform single-cell transcriptomes of 84,363 cells derived from 15 tissue organs of one adult donor and generate an adult human cell atlas. The adult human cell atlas depicts 252 subtypes of cells, including major cell types such as T, B, myeloid, epithelial, and stromal cells, as well as novel COCH + fibroblasts and FibSmo cells, each of which is distinguished by multiple marker genes and transcriptional profiles. These collectively contribute to the heterogeneity of major human organs. Moreover, T cell and B cell receptor repertoire comparisons and trajectory analyses reveal direct clonal sharing of T and B cells with various developmental states among different tissues. Furthermore, novel cell markers, transcription factors, and ligand-receptor pairs are identified with potential functional regulations in maintaining the homeostasis of human cells among tissues. Conclusions The adult human cell atlas reveals the inter- and intra-organ heterogeneity of cell characteristics and provides a useful resource in uncovering key events during the development of human diseases in the context of the heterogeneity of cells and organs.

Abstract Smad4, a key mediator of the transforming growth factor‐β signaling, is mutated or deleted in 20% of pancreatic ductal adenocarcinoma (PDAC) cancers and significantly affects cancer development. However, the effect of Smad4 loss on the immunogenicity and tumor immune microenvironment of PDAC is still unclear. Here, a surprising function of Smad4 in suppressing mouse PDAC tumor immunogenicity is identified. Although Smad4 deletion in tumor cells enhances proliferation in vitro, the in vivo growth of Smad4‐deficient PDAC tumor is significantly inhibited on immunocompetent C57BL/6 (B6) mice, but not on immunodeficient mice or CD8+ cell‐depleted B6 mice. Mechanistically, Smad4 deficiency significantly increases tumor cell immunogenicity by promoting spontaneous DNA damage and stimulating STING‐mediated type I interferon signaling,which contributes to the activation of type 1 conventional dendritic cells (cDC1) and subsequent CD8+ T cells for tumor control. Furthermore, retarded tumor growth of Smad4‐deficient PDAC cells on B6 mice is largely reversed when Sting is codeleted, or when the cells are implanted into interferon‐alpha receptor‐deficientmice or cDC1‐deficientmice. Accordingly, Smad4 deficiency promotes PDAC immunogenicity by inducing tumor‐intrinsic DNA damage‐elicited type I interferon signaling.

Abstract Success in anticancer immune therapy relies on stimulation of tumor antigen‐specific T lymphocytes and effective infiltration of the T cells into tumor tissue. Here, a therapeutic vaccine that promotes proliferation and tumor infiltration of antigen‐specific T cells in both inflamed and noninflamed tumor types is described. The vaccine consists of STING agonist 2′3′‐cGAMP, TLR9 ligand CpG, and tumor antigen peptides that are loaded into nanoporous microparticles (μGCVax). μGCVax is effective in inhibiting lung metastatic melanoma, primary breast cancer, and subcutaneous colorectal cancer in their respective murine models, including functional cure of HER2‐positive breast cancer. Mechanistically, μGCVax potently stimulates type I interferon expression in dendritic cells, and promotes CD8+ and CD103+ dendritic cell maturation and migration to lymph nodes and other lymphatic tissues. Antitumor responses are dependent on TLR9 and interferon α/β receptor signaling, and to a less extent on STING signaling. These results demonstrate a high potential for μGCVax in mediating antitumor immunity in personalized cancer therapy.

Background Dendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy.Methods In vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3−/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment.Results By screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody.Conclusions Our findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.

Background To date, few studies have evaluated the impact of lobectomy versus sublobar resection for early small cell lung cancer (SCLC). We investigated the survival rates of patients with pathological stage T1‐2N0M0 SCLC who underwent lobectomy or sublobar resection. Methods We identified 548 SCLC patients in the Surveillance, Epidemiology, and End Results database who underwent lobectomy or sublobar resection. Propensity score matching (PSM) and Cox regression analysis were used to adjust for baseline characteristics. Results The three‐year overall survival (OS) of patients treated with lobectomy (n = 376, 60%) was significantly higher than those treated with sublobar resection (n = 172, 38%). PSM and Cox multivariable analysis further confirmed this result (hazard ratio [HR] 0.543, 95% confidence interval [CI] 0.421–0.680; P

K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-rasG12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression.Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers.

Abstract Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two‐phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome‐wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta‐analysis of all samples (n = 5553) confirms that the presence of rs1131636‐T, located in the 3′‐UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20–1.47, P = 6.31 × 10−8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR‐1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

Abstract Background Initial primary colorectal cancer (IPCRC) has a high risk of developing into second primary colorectal cancer (SPCRC). Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) have different characteristics and are considered to be two different entities. However, the different risks for SPCRC in categorized tumor sites and SPCRC subcategorized sites have not been fully elucidated to date. We aimed to compare incidence and survival of IPCRC and SPCRC and characterize the risk factors of SPCRC while also comparing the different SPCRC characteristics. Methods We used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data to compute standardized incidence ratios (SIR) in order to estimate risk of SPCRC after IPCRC diagnosis. The most prominent risk factors for SPCRC were measured by multivariate regression analysis and the temporal trend of SPCRC incidence was assessed with Joinpoint regression. Survival of patients with SPCRC and IPCRC was compared by Kaplan-Meier analysis. Results Patients with IPCRC were 1.73 times more likely to develop SPCRC (SIR = 1.73, 95% CI 1.69–1.78). SPCRC incidence declined since the first 8 years of IPCRC diagnosis to baseline. We demonstrated poorer survival with SPCRC compared with IPCRC while second RCC resulted in better survival compared with second LCC. Black ethnicity, age range 70–79, and LCC were associated with the highest risk of developing SPCRC. Conclusion The characteristic differences between second LCC and RCC were relatively narrow. Furthermore, in those with SPCRC, RCC had the best survival outcome.

Background and objective Currently, the prognosis of lobectomy and sub-lobectomy for the treatment of stage Ia small cell lung cancer (SCLC) is rarely reported. We retrospectively studied T1N0M0 (≤3 cm) SCLC patients aged ≥60 years, aiming to comparatively analyze the prognosis of lobectomy and sub-lobectomy in treating patients with Ia SCLC. Methods Patients with stage Ia SCLC diagnosed by pathologic between 1992 and 2010 were selected from the “Surveillance, Epidemiology and End Results database”(SEER). Outcome data were compared using Kaplan-Meier (Log-rank test) and Cox model multivariate analysis. Results We identified 515 patients. Median overall survival (OS) of the lobectomy (n=110), sublobar resection (n=57) and non-surgical (n=348) cohort were 45, 23 and 16 months, respectively. The corresponding 5-year OS of the three groups were 44%, 30%, and 14%, respectively. No significant difference in the prognosis of patients with or without lymph node examination/ dissection (P=0.107) and the 5-year OS of patients underwent lobectomy with chemoradiation was 50%. Cox multivariable analysis showed that operation treatment, including lobectomy and sublobectomy, was one of the independent factors associated with the prognosis of early SCLC patients, and patients undergo lobectomy shows a better OS compared with sublobar resection (Lob vs Sub, HR=0.645; 95%CI: 0.433-0.961, P=0.031). Conclusion For age ≥60 years T1N0M0 (≤3 cm) SCLC patients, we recommend anatomical lobectomy combined with adjuvant chemoradiation.

Abstract Background Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. Methods We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. Results The CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. Conclusions CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.

Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed.

Automatic detection of steel surface defects is very important for product quality control in the steel industry. However, the traditional method cannot be well applied in the production line, because of its low accuracy and slow running speed. The current, popular algorithm (based on deep learning) also has the problem of low accuracy, and there is still a lot of room for improvement. This paper proposes a method combining improved ResNet50 and enhanced faster region convolutional neural networks (faster R-CNN) to reduce the average running time and improve the accuracy. Firstly, the image input into the improved ResNet50 model, which add the deformable revolution network (DCN) and improved cutout to classify the sample with defects and without defects. If the probability of having a defect is less than 0.3, the algorithm directly outputs the sample without defects. Otherwise, the samples are further input into the improved faster R-CNN, which adds spatial pyramid pooling (SPP), enhanced feature pyramid networks (FPN), and matrix NMS. The final output is the location and classification of the defect in the sample or without defect in the sample. By analyzing the data set obtained in the real factory environment, the accuracy of this method can reach 98.2%. At the same time, the average running time is faster than other models.

Micro- and nanometer-size particles have become popular candidates for cancer vaccine adjuvants. However, the mechanism by which such particles enhance immune responses remains unclear. Here, we report a porous silicon microparticle (PSM)-based cancer vaccine that greatly enhances cross-presentation and activates type I interferon (IFN-I) response in dendritic cells (DCs). PSM-loaded antigen exhibited prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Phagocytosis of PSM by DCs induced IFN-I responses through a TRIF- and MAVS-dependent pathway. DCs primed with PSM-loaded HER2 antigen produced robust CD8 T cell-dependent anti-tumor immunity in mice bearing HER2+ mammary gland tumors. Importantly, this vaccination activated the tumor immune microenvironment with elevated levels of intra-tumor IFN-I and MHCII expression, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. These findings highlight the potential of PSM as an immune adjuvant to potentiate DC-based cancer immunotherapy.

The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms by which cells protect themselves from inflammatory signals are unknown. Downregulation of IKKα promotes skin tumor progression from papillomas to squamous cell carcinomas, which is frequently accompanied by genomic instability, including aneuploid chromosomes and extra centrosomes. In this study, we found that IKKα promoted oligomerization of nucleophosmin (NPM), a negative centrosome duplication regulator, which further enhanced NPM and centrosome association, inhibited centrosome amplification, and maintained genome integrity. Levels of NPM hexamers and IKKα were conversely associated with skin tumor progression. Importantly, proinflammatory cytokine-induced IKKα activation promoted the formation of NPM oligomers and reduced centrosome numbers in mouse and human cells, whereas kinase-dead IKKα blocked this connection. Therefore, our findings suggest a mechanism in which an IKKα-NPM axis may use inflammatory signals to suppress centrosome amplification, promote genomic integrity, and prevent tumor progression.

Gene knockout studies unexpectedly reveal a pivotal role for IkB kinase alpha (IKKa) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikka heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKa deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikka floxed mice. On the other hand, transgenic mice overexpressing IKKa in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKa represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKa deletion mediated by a mutation, which generates a stop codon in the Ikka gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKa and Ikka mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKa in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside.