TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy.

BACKGROUND: AT-rich interaction domain 1A (ARID1A) encodes a vital component of switch/sucrose non-fermentable chromatin-remodeling complex. Given its association with genomic instability, we conducted this study to determine whether ARID1A mutation status had an impact on therapeutic responsiveness in gastric cancer (GC), especially combinatory chemo-immunotherapy. METHODS: We retrospectively enrolled a total of 1162 patients from five independent cohorts. ZSHS Cohort and TCGA Cohort were designed to inform chemotherapeutic relevance and immunobiology of ARID1A-mutant GC based on tissue samples and sequencing data, respectively. MSKCC Cohort, mGC Cohort, and Melanoma Cohort were utilized to interrogate the predictive efficacy of ARID1A mutation to programmed cell death protein 1 (PD-1) blockade. RESULTS: ARID1A mutation was enriched in EBV-positive, hypermutated-single nucleotide variant and microsatellite-unstable subtype GC, and was predictive of responsiveness to both fluorouracil-based chemotherapy and PD-1 blockade. Specifically, ARID1A mutation score was a highly sensitive indicator (91%) of response to pembrolizumab. Mechanistically, ARID1A mutation correlated with extensive DNA damage repair deficiency and immunogenic tumor microenvironment (TME) featured by elevated activated subsets of CD8+ T cells, CD4+ T cells, and NK cells. Type 17T helper cells were typically abundant in ARID1A-mutant GC and might be a precondition for chemosensitivity conferred by ARID1A mutation. Furthermore, ARID1A mutation indicated elevated expression of VEGFA and CLDN18, as well as over-representation of ERBB2 and FGFR2 signaling pathway. CONCLUSIONS: ARID1A-mutant GC displayed immunogenic TME and might be a candidate for both monotherapy and the combination of frontline chemotherapy and PD-1 blockade.

Immune inactivation by VISTA predicts clinical outcome and therapeutic benefit in muscle-invasive bladder cancer.

BACKGROUND: V domain Immunoglobulin suppressor of T cell activation (VISTA) has been proved to be a novel immune checkpoint molecule that positively regulates T cell infiltration in several malignancies. However, the clinical impact of VISTA on muscle-invasive bladder cancer (MIBC) patients remains relatively obscure. METHODS: This study enrolled 135 MIBC patients from Zhongshan Hospital (ZSHS) and 391 patients from The Cancer Genome Atlas (TCGA) to examine the VISTA expression and immune contexture based on immunohistochemistry (IHC) staining and CIBERSORT algorithm. Additionally, IMvigor210 Cohort included 195 bladder-derived urothelial carcinoma patients to evaluate the efficacy of immunotherapy. Kaplan-Meier curve and Cox regression analyses were conducted to assess clinical outcomes. RESULTS: MIBC patients with high VISTA+ immune cells (ICs) possessed poor overall survival and inferior therapeutic responsiveness to adjuvant chemotherapy (ACT), but superior responsiveness to PD-L1 inhibitor. VISTA+ ICs infiltration shaped an immunoevasive context featured by regulatory T cells (Tregs), M2 macrophages, mast cells and exhausted CD8+ T cells infiltration, with increased interleukin 10 (IL-10), transforming growth factor-ß (TGF-ß) and interferon-γ (IFN-γ), but also elevated T-cell immunoglobulin mucin-3 (TIM-3), lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and ITIM domain (TIGIT), which was also mainly presented in basal-squamous and luminal-infiltrated subtypes of MIBC. CONCLUSION: VISTA+ ICs infiltration could be an independent predictor to identify poor prognosis and therapeutic responses (PD-L1 blockade and ACT) in MIBC patients, which was associated with immunoevasive contexture. The novel immune checkpoint VISTA might be utilized as a candidate treatment biomarker in MIBC patients.

DC-CNN: Dual-channel Convolutional Neural Networks with attention-pooling for fake news detection.

Fake news detection mainly relies on the extraction of article content features with neural networks. However, it has brought some challenges to reduce the noisy data and redundant features, and learn the long-distance dependencies. To solve the above problems, Dual-channel Convolutional Neural Networks with Attention-pooling for Fake News Detection (abbreviated as DC-CNN) is proposed. This model benefits from Skip-Gram and Fasttext. It can effectively reduce noisy data and improve the learning ability of the model for non-derived words. A parallel dual-channel pooling layer was proposed to replace the traditional CNN pooling layer in DC-CNN. The Max-pooling layer, as one of the channels, maintains the advantages in learning local information between adjacent words. The Attention-pooling layer with multi-head attention mechanism serves as another pooling channel to enhance the learning of context semantics and global dependencies. This model benefits from the learning advantages of the two channels and solves the problem that pooling layer is easy to lose local-global feature correlation. This model is tested on two different COVID-19 fake news datasets, and the experimental results show that our model has the optimal performance in dealing with noisy data and balancing the correlation between local features and global features.

Intra-graph and Inter-graph joint information propagation network with third-order text graph tensor for fake news detection.

Although the Internet and social media provide people with a range of opportunities and benefits in a variety of ways, the proliferation of fake news has negatively affected society and individuals. Many efforts have been invested to detect the fake news. However, to learn the representation of fake news by context information, it has brought many challenges for fake news detection due to the feature sparsity and ineffectively capturing the non-consecutive and long-range context. In this paper, we have proposed Intra-graph and Inter-graph Joint Information Propagation Network (abbreviated as IIJIPN) with Third-order Text Graph Tensor for fake news detection. Specifically, data augmentation is firstly utilized to solve the data imbalance and strengthen the small corpus. In the stage of feature extraction, Third-order Text Graph Tensor with sequential, syntactic, and semantic features is proposed to describe contextual information at different language properties. After constructing the text graphs for each text feature, Intra-graph and Inter-graph Joint Information Propagation is used for encoding the text: intra-graph information propagation is performed in each graph to realize homogeneous information interaction, and high-order homogeneous information interaction in each graph can be achieved by stacking propagation layer; inter-graph information propagation is performed among text graphs to realize heterogeneous information interaction by connecting the nodes across the graphs. Finally, news representations are generated by attention mechanism consisting of graph-level attention and node-level attention mechanism, and then news representations are fed into a fake news classifier. The experimental results on four public datasets indicate that our model has outperformed state-of-the-art methods. Our source code is available at https://github.com/cuibenkuan/IIJIPN.

Integrative tumour mutation burden with CD39 and PD-L1 for the prediction of response to PD-L1 blockade and adjuvant chemotherapy in muscle-invasive bladder cancer patients.

BACKGROUND: CD39, a rate-limiting enzyme to convert extracellular ATP (eATP) to adenosine, has been reported to be a key modulator of immune response, but its correlation with therapeutic sensitivity remains obscure. We conducted this study to determine whether the integration of CD39 and traditional biomarkers could improve the prediction of responsiveness to PD-L1 blockade and platinum-based chemotherapy. METHODS: We retrospectively enrolled a total of 760 patients from IMvigor210 trial, TCGA database and Zhongshan Hospital in this study. We constructed the CPT scoring system based on CD39, PD-L1 and tumour mutation burden (TMB) and validated its efficacy in predicting therapeutic responsiveness in MIBC patients. Kaplan-Meier survival and Cox regression analyses were applied to assess clinical outcomes of patients. RESULTS: The CPT scoring system could predict the response to PD-L1 blockade and platinum-based chemotherapy. The CPT score was positively correlated with APOBEC mutational signature and SNV neoantigens enrichment, antigen presentation, and TCR signalling. High CPT score also indicated the inflamed immune phenotype and basal/squamous molecular subtype. CONCLUSIONS: CD39 expression is closely correlated with the immunogenic contexture of MIBC. Integrating CD39 with PD-L1 and TMB could stratify the sensitivity of patients with MIBC to PD-L1 blockade and platinum-based chemotherapy.

Latency-associated Peptide Identifies Immunoevasive Subtype Gastric Cancer With Poor Prognosis and Inferior Chemotherapeutic Responsiveness.

OBJECTIVE: To examine the clinical significance of LAP to predict survival outcomes and chemotherapeutic responsiveness in gastric cancer. BACKGROUND: LAP has been shown to possess significant immunoregulatory roles in several malignancies. However, the role and clinical significance of LAP in gastric cancer still remains unknown. METHODS: Four hundred and fifty-six tumor tissue microarray specimens, 80 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, Fudan University and transcriptomic and clinical data of 328 gastric cancer patients from the Cancer Genome Atlas were analyzed. LAP expression and immune contexture were examined by immunohistochemistry, CIBERSORT, and flow cytometry. Clinical outcomes of patient subgroups were compared by Kaplan-Meier curves, Cox model and interaction test. RESULTS: High LAP expression predicted poor overall survival (P < 0.001, P < 0.001, and P = 0.022) and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (P = 0.008 for interaction) in gastric cancer. LAP was associated with immunoevasive tumor microenvironment featured by dysfunctional CD8+ T cells infiltration (P < 0.001). The LAP-associated dysfunctional CD8+ T cells had an exhausted phenotype with decreased effector molecules such as interferon-γ, granzyme B, and perforin, but also elevated programmed cell death protein-1, which resulted in poor prognosis and inferior therapeutic responsiveness. CONCLUSIONS: This study revealed that LAP could identify immunoevasive subtype gastric cancer, indicating LAP might be a potential immunotherapeutic target and facilitate patient counseling on individualized adjuvant therapy and follow-up scheduling in gastric cancer.

Poor Clinical Outcomes and Immunoevasive Contexture in Intratumoral IL-10-Producing Macrophages Enriched Gastric Cancer Patients.

OBJECTIVE: To investigate the clinical significance of IL-10+ tumor-associated macrophages (TAMs) in gastric cancer. BACKGROUND: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10+ TAMs in gastric cancer remains obscure. METHODS: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10+ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan-Meier curves and Cox model. RESULTS: Gastric cancer patients with high IL-10+ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10+ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8+ T cell dysfunction. The combinational analysis of IL-10+ TAM and CD8+ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10+ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer. CONCLUSIONS: This study revealed that IL-10+ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy, indicating IL-10+ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.

Intratumoral Foxp3+RORγt+ T cell infiltration determines poor prognosis and immunoevasive contexture in gastric cancer patients.

BACKGROUND: Foxp3+RORγt+ T cells possess both characteristics of regulatory T cells and T helper 17 cells and show significant immunoregulatory functions in autoimmune diseases. However, the role and clinical significance of Foxp3+RORγt+ T cells in gastric cancer remains unclear. METHODS: We enrolled 452 gastric cancer tissue microarray samples and 60 fresh tumor tissue samples from Zhongshan Hospital. The infiltration of Foxp3+RORγt+ T cells and immune contexture were examined by immunohistochemistry and flow cytometry. Survival analyses of patient subgroups were conducted by Kaplan-Meier curves, log-rank test and Cox proportional model. RESULTS: High infiltration of Foxp3+RORγt+ T cells predicted poor overall survival (P = 0.0222 and 0.0110) and inferior therapeutic response (P = 0.003 for interaction) in gastric cancer. Foxp3+RORγt+ T cells were associated with impaired effective function of CD8+ T cells featured by decreased interferon-γ, granzyme B and CD107a expression. Co-evaluation of Foxp3+RORγt+ T cells and CD8+ T cells could predict survival outcomes and chemotherapeutic responsiveness more precisely. CONCLUSIONS: We found that Foxp3+RORγt+ T cells could potentially attenuate effective functions of CD8+ T cells and led to adverse survival outcomes and inferior chemotherapeutic responsiveness. Moreover, the novel co-evaluation system might be useful for prognosis prediction for appropriate treatment in gastric cancer. NOVELTY AND IMPACT STATEMENTS: Clinical significance of Foxp3+RORγts+ T cells has not been studied in gastric cancer. Herein, we investigated the prognostic value of Foxp3+RORγt+ T cells in 452 patients. We demonstrated that intratumoral Foxp3+RORγt+ T cell infiltration was a prognostic biomarker for overall survival and the identification of patients might benefit from post-gastrectomy 5-fluorouracil. These findings allow a more precise stratification upon the co-evaluation with CD8+ T cells to better clinical management for patients who would benefit from 5-fluorouracil.

CD47 expression in gastric cancer clinical correlates and association with macrophage infiltration.

BACKGROUND: CD47 has been identified as an innate immune checkpoint and found to be associated with inferior survival in various types of cancer. However, the critical role of CD47 in gastric cancer and its association with tumor associated macrophages remain unclear. METHODS: Tumor tissues of gastric cancer from Zhongshan Hospital and data from GSE62254, GSE84437 and TCGA datasets were analyzed. Immunohistochemistry was performed to detect the expression of CD47, CD11c, CD163 and CD68 in gastric cancer tissues. Kaplan-Meier curves and Cox model were used for comparing the clinical outcomes of patients belonging to different subgroups. RESULTS: Gastric cancer patients with high CD47 expression exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (ACT). A positive correlation was found between M1-polarized macrophage infiltration and CD47 expression in gastric cancer; however, the prognostic value of M1-polarized macrophages was attenuated in CD47-high gastric cancer patients. Moreover, we found that CD47 mRNA level was enriched in microsatellite-instable (MSI) subtype of gastric cancer and associated with ARID1A mutation and FGFR2 signaling pathway activation. CONCLUSIONS: Aberrant CD47 expression represented an independent predictor for adverse survival outcome and ACT resistance in gastric cancer. Targeting CD47 might be a promising strategy for gastric cancer patients.

In Vitro Activity of Imipenem/Relebactam Against Enterobacteriaceae Isolates Obtained from Intra-abdominal, Respiratory Tract, and Urinary Tract Infections in China: Study for Monitoring Antimicrobial Resistance Trends (SMART), 2015-2018.

BACKGROUND: Considering the increasing incidence of carbapenem-resistant Enterobacteriaceae in China, this study aimed to establish the in vitro effectiveness of imipenem/relebactam (IMI/REL) on clinical Enterobacteriaceae isolates derived from intra-abdominal infections (IAIs), respiratory tract infections (RTIs), and urinary tract infections (UTIs) in China between 2015 and 2018. METHODS: In total, 8781 Enterobacteriaceae isolates from IAI, RTI, and UTI samples were collected from 22 hospitals across 7 geographic regions of China. Susceptibility to antimicrobial drugs was tested using the Clinical and Laboratory Standards Institute broth microdilution and breakpoints, and IMI/REL activity was assessed using United States Food and Drug Administration guidelines. RESULTS: In 2015-2018, the most frequently identified Enterobacteriaceae species was Escherichia coli (n = 4676 [53.3%]), followed by Klebsiella pneumoniae (n = 2949 [33.6%]) and Enterobacter cloacae (n = 542 [6.2%]). The Enterobacteriaceae isolates showed 95.2% overall susceptibility to IMI/REL, of which the susceptibility rates in isolates from IAI, RTI, and UTI were 95.8%, 91.4%, and 96.6%, respectively. Overall, the susceptibilities of both intensive care unit (ICU) and non-ICU Enterobacteriaceae isolates to colistin were 92.9%, followed by IMI/REL (90.7% [95.9%]) and amikacin (83.3% [92.3%]). In addition, IMI/REL restored 66.3% susceptibility in imipenem-nonsusceptible Enterobacteriaceae. CONCLUSIONS: Given their high in vitro susceptibility, Enterobacteriaceae infections in China should be considered for IMI/REL treatment, especially with isolates that are not susceptible to carbapenems.

Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses.

Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.

Identification and validation of an immunogenic subtype of gastric cancer with abundant intratumoural CD103+CD8+ T cells conferring favourable prognosis.

BACKGROUND: Intratumoural CD103+CD8+ T cells have been linked to prolonged survival in several malignancies. However, the clinical significance of CD103+CD8+ T cells in gastric cancer remains unexplored. METHODS: Gastric cancer tissues from Zhongshan Hospital and data from Gene Expression Omnibus were obtained and analysed. Immunohistochemistry and flow cytometry were performed to detect the number and phenotypical characteristics of CD103+CD8+ T cells. The effect of programmed cell death protein-1 (PD-1) blockade on CD103+CD8+ T cells was evaluated with the use of an in vitro study based on fresh tumour tissues. RESULTS: CD103+CD8+ T cells predicted superior overall survival and provided better prognostic power than total CD8+ T cells in gastric cancer. Patients with high CD103+CD8+ T cell infiltration also gained more benefit from adjuvant chemotherapy. Flow cytometry analysis showed that CD103+CD8+ T cells exerted superior anti-tumour effects with stronger retention capacity and cytotoxicity. Moreover, an in vitro study showed that CD103+CD8+ T cells were more functionally restored after PD-1 blockade than CD103-CD8+ T cells. CONCLUSIONS: CD103+CD8+ T cells might be a useful marker to predict prognosis and therapeutic efficacy for gastric cancer patients. Efforts to increase intratumoural CD103+CD8+ T cell frequency might be a novel therapeutic strategy in gastric cancer.

Tumor-infiltrating CD39+CD8+ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients.

PURPOSE: Tumor microenvironment is important in the progression of clear cell renal cell carcinoma (ccRCC), and its prognostic value is still unclear. Recent reports demonstrated tumor-infiltrating CD39+CD8+ T cells are abundant, but their function remains obscure. We aim to assess clinical value of CD39+CD8+ T cells and seek a potential therapeutic target in ccRCC. EXPERIMENTAL DESIGN: We immunohistochemically evaluated clinical value of CD39+CD8+ T cells in a retrospective Zhongshan Hospital cohort of 243 ccRCC patients. Fresh tumor samples (n = 48), non-tumor tissues and peripheral blood for flow cytometry analyses were collected to analyze immune cell functions from Zhongshan Hospital. The survival benefit of tyrosine kinase inhibitors (TKIs) in this subpopulation was evaluated. Kaplan-Meier analysis and COX regression model were applied for survival analyses. Bioinformatics analysis performed in TCGA KIRC cohort and the scRNA-seq cohort. RESULTS: We found that accumulation of CD39+CD8+ T cells indicated poor prognosis (p < 0.0001) and indicated therapeutic benefit of TKIs therapy (p = 0.015). CD39+CD8+ T cells showed decreased TNF-α and IFN-γ with elevated PD-1 and TIM-3 expression. Further analysis of tumor-infiltrating immune cell landscape in the ccRCC revealed the positive correlation between CD39+CD8+ T cells and Tregs (p = 0.037) and M2-polarized macrophages (p < 0.0001). Finally, inhibition of CD39 partially restores the anti-tumor function of CD8+ T cells. CONCLUSIONS: High CD39+CD8+ T cells indicated poor prognosis in ccRCC, due to impaired anti-tumor function of CD39+CD8+ T cells and indicated therapeutic benefit of TKIs therapy.

Lauren classification identifies distinct prognostic value and functional status of intratumoral CD8+ T cells in gastric cancer.

With dichotomous etiology and pathogenesis, intestinal type and diffuse type gastric cancers vary in their clinical and molecular features to the point of representing distinct entities. However, the differences of tumor-infiltrating immune cells within the two types of gastric cancer have not been well researched. This study was aimed to evaluate the functional impact of Lauren classification on immune contexture in gastric cancer patients. Tumor tissues of gastric cancer patients from Zhongshan Hospital and gastric cancer data from The Cancer Genome Atlas (TCGA) cohort were analyzed. By immunohistochemistry and flow cytometry, we found that intratumoral CD8+ T cells were more abundant but less functional in diffuse type as compared with those in intestinal type tumor tissues. Survival analysis indicated that CD8+ T cells yielded favorable prognosis only in intestinal type patients other than diffuse type cancer patients. Moreover, such diffuse type-associated CD8+ T cell dysfunction was featured by elevated expression of immunosuppressive factors including interleukin-10 (IL-10), transforming growth factor-ß1 (TGF-ß1) and indoleamine 2,3-dioxygenase 1 (IDO1). In summary, we found that the density, prognostic significance and functional status of intratumoral CD8+ T cells varied with Lauren subtypes in gastric cancer. These results further indicated Lauren classification might be a potential therapeutic marker, and should be considered in therapeutic decisions, especially immunotherapeutic eligibility.

Fetal magnetic resonance imaging contributes to the diagnosis and treatment of meconium peritonitis.

BACKGROUND: Meconium peritonitis (MP) is a rare fetal disease that needs to be urgently identified for surgical intervention. We report a series of 35 patients diagnosed prenatally with MP by magnetic resonance imaging (MRI), illustrate the imaging findings and investigate the predictive value of these findings for postpartum management. METHOD: A consecutive cohort of patients diagnosed with MP who were born at our institution from 2013 to 2018 was enrolled retrospectively. The prenatal ultrasound and MRI findings were analyzed. Fisher's exact probability test was used to evaluate the predictive value of MRI for surgical intervention between the operative group and the nonoperative group. RESULTS: Ascites (30/35) and distended bowel loops (27/35) were two of the most common prenatal MP-related findings on fetal MRI. Of the 35 infants, 26 received surgical intervention. All fetuses with MRI scans showing bowel dilatation (14/26, p = 0.048) and micro-colorectum (13/26, p = 0.013) required surgery. There were no significant differences in the number of fetuses with meconium pseudocysts and peritoneal calcifications between the two groups. CONCLUSION: Fetuses with bowel dilatation and micro-colorectum on MRI may need postpartum surgical intervention. Infants with only a small amount of ascites and slight bowel distention were likely to receive conservative treatment.

Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer.

OBJECTIVE: Our previous studies have identified CXCL8 as the crucial chemokine responsible for gastric cancer metastasis mediated by loss of RACK1. However, the regulatory effect of CXCL8 on immune surveillance in gastric cancer remains obscure. DESIGN: Flow cytometry analyses were performed to examine major source of CXCL8 and phenotypes of immune cells in fresh tumour tissues from 76 patients with gastric cancer. Real-time PCR was performed to analyse CXCL8 mRNA level in gastric cancer tissues. For immunohistochemical analyses, a total of 420 patients with gastric cancer undergoing curative resection were enrolled. In vitro culture of fresh tumour tissue was performed to evaluate the potential therapeutic effect of blocking CXCL8 pathway in gastric cancer. RESULTS: Increased level of CXCL8 indicates poor clinical outcome and tumour progression in patients with gastric cancer. In gastric cancer tissues, CXCL8 is predominantly secreted by macrophages and colony stimulating factor 2 (CSF-2) facilitates macrophage-derived CXCL8 secretion. High level of CXCL8 is associated with decreased CD8+ T cells infiltration and Ki67+ CD8+ T cells proportion. Moreover, CXCL8 also inhibits CD8+ T cells function by inducing the expression of PD-L1 on macrophages. Finally, we show that a small-molecule CXCR2 inhibitor, reparixin, drives the decreased programmed death-ligand 1 (PD-L1+) macrophages and promotes antitumour immunity. Accordingly, high levels of CXCL8+ macrophages are positively correlated with poor prognosis in patients with gastric cancer. CONCLUSIONS: CXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1+ macrophages in gastric cancer. CXCL8 inhibitors may drive antitumour response, providing potential therapeutic effects for patients with gastric cancer.

CD19+ tumor-infiltrating B-cells prime CD4+ T-cell immunity and predict platinum-based chemotherapy efficacy in muscle-invasive bladder cancer.

PURPOSE: CD19+ tumor-infiltrating B-cells (CD19+ TIB) play a crucial role in tumorigenesis, but their clinical relevance in muscle-invasive bladder cancer (MIBC) remains unknown. This study aimed to investigate the prognostic value of CD19+ TIB for post-surgery survival and adjuvant chemotherapy response in MIBC. EXPERIMENTAL DESIGN: We assessed TIB by immunohistochemical staining of CD19 in 246 MIBC patients from Zhongshan Hospital and Shanghai Cancer Center. We evaluated the survival benefit of platinum-based chemotherapy according to CD19+ TIB. The mechanism underlying CD19+ TIB antitumor immunity was explored through the Cancer Genome Atlas (TCGA) dataset analysis and an in vitro Ag presentation assay. RESULTS: CD19+ TIB extensively infiltrated into the tumor stroma of MIBC. Adjuvant chemotherapy (ACT) led to a significantly increased benefit in the high CD19+ TIB MIBC patients (P = 0.003). In multivariate analysis, high CD19+ TIB MIBC patients had significantly longer OS with ACT in the discovery set (HR = 0.487, P = 0.038). TCGA gene expression analyses showed enrichment of adaptive immunity, T-cell-mediated immunity, and antigen-presentation signaling pathways in high CD19+ TIB MIBC patients. Moreover, CD19+ TIB co-localized with activated CD4+ TIT and expressed surface markers characteristic of antigen-presenting cells. Finally, an antigen-presentation assay demonstrated the antigen-presentation function of CD19+ TIB. CONCLUSION: CD19+ TIB was identified as an independent prognostic factor, which could predict for post-surgery survival and platinum-based ACT benefits in MIBC. CD19+ TIB serve as antigen-presenting cells (APCs) to activate CD4+ TIT in the tumor environment of MIBC.