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Abstract For reasons not completely clear, natural killer (NK) cells from tumor patients displayed multiple exhaustion features and could not be completely restored even when the inhibitory signals from the intratumoral environment had ceased to exist. Here, we found that the circulating NK cells from bladder cancer patients presented significantly reduced cytotoxicity than the circulating NK cells from healthy volunteers. This impairment in cytotoxicity resulted in part from an overrepresentation of Tim-3+ NK cells in bladder cancer patients. Interestingly, patients with higher frequency of Tim-3+ NK cells tended to present higher frequency of Gal-9+ cells in tumor. Exogenous Gal-9 significantly reduced the cytotoxicity of Tim-3+, but not Tim-3-, NK cells. Patients with better prognosis presented lower levels of Tim-3+ NK cells and Gal-9+ tumor cells. We then attempted to improve the cytotoxicity of NK cells using a combination of exogenous cytokines. IL-2 + IL-15 and IL-2 + IL-21 significantly enhanced, but could not completely restore, the cytotoxicity of NK cells in bladder cancer patients. Notably, when the cytokine concentration increased from intermediate levels to high levels, the cytotoxicity of NK cells from healthy volunteers significantly increased with a strong upward trend, whereas the cytotoxicity of NK cells from bladder cancer patients plateaued at intermediate levels. Further examination revealed that high cytokine concentration significantly increased the Tim-3 expression in NK cells from bladder cancer patients. Blocking Tim-3 not only improved the cytotoxicity of NK cells from bladder cancer patients, but also eliminated the plateauing effect when the NK cells were stimulated with high concentrations of cytokines. Together, these data suggested that proinflammatory cytokines could moderately improve NK cell cytotoxicity in bladder cancer patients. However, the effect was limited due to a concurrent upregulation of Tim-3. Highlights • NK cells from bladder cancer patients presented significant Tim-3 upregulation. • NK cells from bladder cancer patients presented significantly reduced cytotoxicity. • Cytokine-mediated stimulatory effects were less potent in bladder cancer patients. • Treatment with cytokines increased the expression of Tim-3 by NK cells. • Tim-3 blockade allowed the NK cells to present higher cytotoxicity in patients. [ABSTRACT FROM AUTHOR]

Background Tumor-associated macrophages (TAMs) are associated with poor outcomes in multiple solid cancers and play important roles in cancer progression. Epithelial-mesenchymal transition (EMT) may account for metastasis and recurrence. However, the association between TAMs and EMT is not clarified in triple-negative breast cancer (TNBC). The aim of this study was to investigate the effects of TAMs on EMT in TNBC. Material and methods We studied specimens from 278 patients with TNBC. TAMs marker cluster of differentiation 163 and EMT-related marker E-cadherin were detected by immunohistochemistry in TNBC tissues, and their clinical significance was evaluated from the patients' medical records. Results TNBC patients with polarized cluster of differentiation 163 + TAMs infiltration and low level of E-cadherin had a significantly higher risk of aggressive features, including recurrence, histologic differentiation, and lymph node metastasis. Infiltration of TAMs was also negatively correlated with E-cadherin in TNBC tissues. Multivariate analysis indicated that infiltration of TAMs and low expression of E-cadherin were independent prognostic factors of overall survival and disease-free survival in TNBC patients. Conclusions High infiltration of TAMs was associated with low expression of E-cadherin and could be used as an unfavorable prognostic factor for patients with TNBC. [ABSTRACT FROM AUTHOR]

The genome-wide profiling of 5-hydroxymethylcytosines (5hmC) on circulating cell-free DNA (cfDNA) has revealed promising biomarkers for various diseases. The purpose of this study was to investigate 5hmC signals in serum cfDNA and identify novel predictive biomarkers for the development of chemoresistance in high-grade serous ovarian cancer (HGSOC). We hypothesized that 5hmC profiles in cfDNA reflect the development of chemoresistance and elucidate pathways that may drive chemoresistance in HGSOC. Moreover, we sought to identify predictors that would better stratify outcomes for women with intermediate-sensitive HGSOC. Women diagnosed with HGSOC and known platinum sensitivity status were selected for this study. Nano-hmC-Seal was performed on cfDNA isolated from archived serum samples, and differential 5hmC features were identified using DESeq2 to establish a model predictive of chemoresistance. A multivariate model consisting of three features (preoperative CA-125, largest residual implant after surgery, 5hmC level of OSGEPL) , stratified samples from intermediate sensitive, chemo-naive women diagnosed with HGSOC into chemotherapy-resistant- and sensitive-like strata with a significant difference in overall survival (OS). Independent analysis of The Cancer Genome Atlas data further confirmed that high OSGEPL1 expression is a favorable prognostic factor for HGSOC. We have developed a novel multivariate model based on clinico-pathologic data and a cfDNA-derived 5hmC modified gene, OSGEPL1 , that predicted response to platinum-based chemotherapy in intermediate-sensitive HGSOC. Our multivariate model applies to chemo-naïve samples regardless if the patint was treated with adjuvant or neoadjuvant chemotherapy. These results merit further investigation of the predictive capability of our model in larger cohorts. • Chemotherapy does not alter global 5hmC deposition patterns on genomic features. • Neoadjuvant-treated platinum resistant disease is enriched in pathways associated with cellular responses to stress. • Adjuvant-treated platinum resistant disease is enriched in pathways associated with drug- and metabolism pathways. • An adjuvant chemotherapy-specific model stratifies intermediate sensitive disease into resistant- and sensitive-like groups. [ABSTRACT FROM AUTHOR]

Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive type of endocervical adenocarcinoma (ECA) with distinct histopathologic features and unfavorable treatment outcomes, but no genomic prognostic factor has been revealed. We aimed to systematically investigate the somatic alterations of GCA at genome-wide level and evaluate their prognostic value. We performed whole-exome sequencing (WES) on 25 pairs of tumor and matched normal samples to characterize the genomic features of Chinese patients with GCA and investigated their relations to histopathological characterizations and prognosis. The prognostic value of the genomic alterations was evaluated in a total of 58 GCA patients. Mutations were commonly observed in reported GCA-related driver genes, including TP53 (32%), CDKN2A (20%), SKT11 (20%), BRCA2 (12%), SMAD4 (12%), and ERBB2 (12%). Recurrent novel trunk mutations were also observed in PBRM1 (12%), FRMPD4 (12%), and NOP2 (8%) with high variant allele frequency. Moreover, enrichment of the APOBEC signature was attributed to frequent gain of somatic copy number alteration (SCNA) of APOBEC3B (20%), which perfectly matched the nuclear-positive staining of APOBEC3B through immunohistochemistry. In contrast, APOBEC3B alteration was absent in patients with conventional type of ECA (N = 52). Notably, positive APOBEC3B was consistently enriched in patients with favorable prognosis in both the discovery cohort and an additional 33 GCA patients, thus indicating a significant association with lower relapse risk of GCA independent of cancer stage (P = 0.02). Our results can aid understanding of the molecular basis of GCA in the Chinese population by providing genomic profiles and highlighting the potential prognostic value of APOBEC3B for GCA through routine clinical IHC. • Novel somatic mutations in several driver genes can be revealed in GCA by whole genome sequencing. • Somatic copy number gain of APOBEC3B was common in GCA, which is rare in conventional endocervical cancer. • Positive immunohistochemistry staining of APOBEC3B can be served as biomarker for favorable prognosis of GCA. [ABSTRACT FROM AUTHOR]

poorly cohesive (PC) gastric cancer (GC) (PC-GC) is a distinct histological subtype of GC and is defined as a tumor consisting of isolated or small clusters of tumor cells with poorly differentiated and metastatic characteristics. According to multiple studies, PC-GC is intrinsically heterogeneous, with mesenchymal variants being the most aggressive. However, to date, the molecular mechanisms associated with PC-GC are still not fully understood. This study investigated the role of the USP51/ZEB1/ACTA2 axis in promoting GC metastasis. Single-cell sequencing revealed that E-box binding homeobox 1 (ZEB1) expression was significantly increased in a subpopulation of low-adherent cells and was an independent prognostic factor in GC patients. Furthermore, the bulk transcriptome analysis revealed a significant positive correlation between Ubiquitin Specific Peptidase 51 (USP51), ZEB1, and Actin Alpha 2 (ACTA2), and our data further confirmed that all three were highly co-localized in PC-GC tissues. According to the findings of in vitro and in vivo experiments, USP51 was able to maintain ZEB1 expression to promote ACTA2 transcription, thereby activating the mesenchymal phenotype of GC cells and promoting tumor metastasis. Moreover, USP51 could recruit and activate stromal cells, including M2-like macrophages and fibroblasts, through cancer cells. Clinical data suggested that overexpression of USP51 predicts that patients have difficulty benefiting from immunotherapy and is associated with immune-exclusion tumor characteristics. Collectively, the findings of this study shed light on a key mechanism by which elevated USP51 expression induces Epithelial-mesenchymal transition (EMT) in GC cells, hence facilitating GC cell proliferation, survival, and dissemination. In this view, USP51/ZEB1/ACTA2 may serve as a candidate therapeutic target against GC metastasis. [Display omitted] [ABSTRACT FROM AUTHOR]

• Accurate prognostic prediction for head and neck cancer is important for clinics. • Compared with the traditional Cox regression algorithm, machine learning techniques can reflect the nonlinear associations that exist in clinical practice. • Among the machine learning techniques, random forest performs best in survival predictions of Head and Neck cancer. Accurate prognostic prediction for head and neck cancer (HNC) is important for the improvement of clinical management. We aimed to compare the prognostic value of various machine learning techniques (MLTs) and statistical Cox regression model for different types of HNC. Clinical data of HNC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 1974 to 2016. The prediction performance of five ML models, including random forest (RF), gradient boosting decision tree (GBDT), support vector machine (SVM), neural network (NN) and deep learning (DL), were compared with the statistical Cox regression model by estimating the concordance index (C-index), integrated Brier score (IBS), time-dependent receiver operating characteristic (ROC) curve and the area under the curve (AUC). Our results showed that the RF model outperformed all other models in prognostic prediction for all tumor sites of HNC, particularly for major salivary gland cancer (MSGC, C-index: 88.730 ± 0.8700, IBS: 7.680 ± 0.4800), oral cavity cancer (OCC, C-index: 84.250 ± 0.6700, IBS: 11.480 ± 0.3300) and oropharyngeal cancer (OPC, C-index: 82.510 ± 0.5400, IBS: 10.120 ± 0.1400). Meanwhile, we analyzed the importance of each clinical variable in the RF model, in which age and tumor size presented the strongest positive prognostic effects. Additionally, similar results can be observed in the internal (6th edition of the AJCC TNM staging system cohort) and external validations (the TCGA HNC cohort). The RF model is a promising prognostic prediction tool for HNC patients, regardless of the anatomic subsites. [ABSTRACT FROM AUTHOR]

Recent studies suggest that the human trophoblast cell-surface antigen TROP2 is highly expressed in a number of tumours and is correlated with poor prognosis. However, its role in non-small cell lung carcinoma (NSCLC) remains largely unknown. Here we examined TROP2 expression by immunohistochemistry in a series of 68 patients with adenocarcinoma (ADC). We found significantly elevated TROP2 expression in ADC tissues compared with normal lung tissues (P < 0.05), and TROP2 overexpression was significantly associated with TNM (tumour, node, metastasis) stage (P = 0.012), lymph node metastasis (P = 0.038), and histologic grade (P = 0.013). Kaplan–Meier survival analysis revealed that high TROP2 expression correlated with poor prognosis (P = 0.046). Multivariate analysis revealed that TROP2 expression was an independent prognostic marker for overall survival of ADC patients. Moreover, TROP2 overexpression enhanced cell proliferation, migration, and invasion in the NSCLC cell line A549, whereas knockdown of TROP2 induced apoptosis and impaired proliferation, migration, and invasion in the PC-9 cells. Altogether, our data suggest that TROP2 plays an important role in promoting ADC and may represent a novel prognostic biomarker and therapeutic target for the disease. [ABSTRACT FROM AUTHOR]

The critical role of long non-coding RNAs (lncRNAs) has been implicated in prostate cancer (PCa). As one of them, LINC00992 (LNC992) has been revealed by bioinformatics prediction to be significantly overexpressed in PCa. However, the underlying mechanism of LNC992 in PCa has not been well investigated. First, gene expression microarrays of prostate adenocarcinoma (PRAD) were downloaded from the GEO database, and differentially expressed genes were analyzed. Subsequently, we assessed the LNC992 expression in PCa patients. PCa cells with overexpression or low expression of LNC992 were generated, followed by the examination of proliferation, invasion and migration in vitro and in vivo. The differentially expressed genes were analyzed by microarrays after altering LNC992 expression in PCa cells, and the downstream regulatory mechanisms of LNC992 were analyzed by bioinformatics analysis and validated by RIP and RNA pull-down assays. LNC992 was highly expressed in the PRAD database and in cancer tissues from PCa patients, serving as a poor prognostic factor for PCa patients. Knockdown of LNC992 significantly inhibited PCa cell growth, metastasis, and angiogenesis in vitro and in vivo. Moreover, we found that knockdown of LNC992 significantly suppressed SOX4 expression in cells and that LNC992 could bind to EIF4A3 and promote the translation of SOX4. Inhibition of either EIF4A3 or SOX4 significantly suppressed the growth and metastasis of PCa cells. LNC992 elevates SOX4 expression by binding to SOX4 mRNA and recruiting translation initiation factor EIF4A3, thereby promoting the growth and metastasis of PCa cells in vitro and in vivo. • LNC992 is significantly overexpressed in PCa and is associated with poor prognosis. • LNC992 is associated with the malignant biological behavior of PCa cells. • LNC992 can positively regulate the expression of SOX4. • LNC992 binds to EIF4A3. • SOX4 abrogates the repressive effects of sh-LNC992 on the PCa cell viability. [ABSTRACT FROM AUTHOR]

Although emerging cell- or animal-based evidence supports the relationship between SND1 and cancers, no pan-cancer analysis is available. We thus first explored the potential oncogenic roles of SND1 across thirty-three tumors based on the datasets of TCGA (The cancer genome atlas) and GEO (Gene expression omnibus). SND1 is highly expressed in most cancers, and distinct associations exist between SND1 expression and prognosis of tumor patients. We observed an enhanced phosphorylation level of S426 in several tumors, such as breast cancer or lung adenocarcinoma. SND1 expression was associated with the CD8 + T-cell infiltration level in colon adenocarcinoma and melanoma, and cancer-associated fibroblast infiltration was observed in other tumors, such as bladder urothelial carcinoma or testicular germ cell tumors. Moreover, protein processing- and RNA metabolism-associated functions were involved in the functional mechanisms of SND1. Our first pan-cancer study offers a relatively comprehensive understanding of the oncogenic roles of SND1 across different tumors. • A first pan-cancer analysis of SND1. • SND1 is differentially associated with the prognosis of different tumor cases. • The link between SND1 and CD8+ T-cell or cancer-associated fibroblast infiltration. • An enhanced phosphorylation level of S426 in several tumors, such as breast cancer. • Protein/RNA metabolism-associated issue is involved in the oncogenic role of SND1. [ABSTRACT FROM AUTHOR]

Recent studies suggest that several bacterial species are involved in tumor immunosurveillance and antitumor immunity. The role of bacteria in immune responses in HBV-related hepatocellular carcinoma (HCC) patients is still unknown. In this study, we examined the bacteria-reactive CD8 + T cell response in patients with HBV-related HCC. We found that circulating CD8 + T cells from healthy individuals demonstrated minimal or zero specificity toward a series of commensals and bacteria previously associated with antitumor effects, including Escherichia coli , Enterococcus faecium , Bifidobacterium longum , Bacteroides fragilis , and Enterococcus hirae . In contrast, the circulating CD8 + T cells from HBV-related HCC patients presented significantly elevated bacteria-reactive responses, albeit with high variations among different HCC individuals. Reactivity toward bacteria was also identified in tumor-infiltrating CD8 + T cells. These bacteria-reactive responses were not primarily induced by TLR ligand, but were dependent on the presence of antigen-presenting monocytes, and were MHC class I-restricted. Interestingly, we observed that the CD8 + T cell-to-Foxp3 + regulatory T cell ratio was positively correlated with the proportions of Bifidobacterium longum -reactive and Enterococcus hirae -reactive CD8 + T cells, while the frequency of PD-1 + CD8 + T cells was negatively correlated with the frequency of Enterococcus hirae -reactive CD8 + T cells. Furthermore, the disease-free survival time of HCC patients after tumor resection was positively correlated with the frequencies of Bifidobacterium longum -reactive and Enterococcus hirae -reactive CD8 + T cells. Together, these results suggested that certain bacterial species might present valuable antitumor effects. [ABSTRACT FROM AUTHOR]

Objective To identify novel prognostic and therapeutic markers for PARP inhibitors in BRCA wild type ovarian cancer (OvCa). Methods BRCAness status was defined by analyzing whole-exome deep sequencing data from 220 BRCAwt OvCa cases in TCGA. Thirty-three DNA-repair genes were screened in an integrated manner for BRCA-independent mechanism of BRCAness using multiple-dimensional genomic data. Publicly available databases and siRNA knock-down were used for external validation and evaluation of drug response in OvCa cell lines. Results In 220 BRCAwt OvCa patients, tumors exhibiting the BRCAness signature have enhanced OS (HR [95% CI] = 0.33 [0.15–0.69], P = 0.004) and PFS (HR [95% CI] = 0.51 [0.24–1.08], P = 0.077), strongly suggesting a BRCA-independent mechanism of drug sensitivity in those patients. Systematic screening of driving molecular events of BRCAness revealed that RAD50 deletion is a marker of BRCAness. The RAD50 deletion occurred in 18% of BRCAwt OvCa patients. RAD50 deletion led to its decreased mRNA expression in tumors (fold change = 0.63, P = 3.56 × 10 − 13 ). In BRCAwt patients, RAD50 deletion was associated with significantly better OS (HR [95% CI] = 0.44 [0.25–0.78], P = 0.005) and PFS (HR [95% CI] = 0.60 [0.37–0.99], P = 0.044), adjusted by age and stage. Knockdown of RAD50 expression augmented OvCa cell's responses to cisplatin and olaparib. Among 19 OvCa cell lines, the RAD50 copy number deletion is significantly associated with better responses to two structurally distinct PARPis (i.e. olaparib and rucaparib). Conclusion Our study identified the copy number deletion of RAD50 as a candidate marker for survival and response to PARPis in BRCAwt OvCa tumors. [ABSTRACT FROM AUTHOR]