Interleukin-11Rα2 in the hypothalamic arcuate nucleus affects depression-related behaviors and the AKT-BDNF pathway.

Depression is a widespread emotional disorder with complex pathogenesis. An essential function of the hypothalamus is to regulate emotional disorders. However, further investigation is required to identify the pathogenic genes and molecular mechanisms that contribute to the onset of depression within the hypothalamus. Through RNA-sequencing analysis, this study identified the upregulated expression of interleukin-11 receptor alpha 2 (IL-11Rα2) in the hypothalamus of mice with chronic unpredictable stress (CUS)-induced depression. This substantial increase in IL-11Rα2, not IL-11Rα1 expression levels in the hypothalamus under the influence of CUS was found to be associated with depression-related behaviors. We further showed that IL-11Rα2 is expressed in the arcuate nucleus (ARC) proopiomelanocortin (POMC) neurons of the hypothalamus. Male and female mice exhibited behaviors association with depression, when IL-11Rα2 or its ligand IL-11 was overexpressed in the ARC POMC neurons through the action of an adeno-associated virus. In addition, reductions in the expression levels of proteins involved in the protein kinase B signaling pathways and brain-derived neurotrophic factor were observed upon overexpression of IL-11Rα2 in the hypothalamic ARC. This study emphasizes the importance of IL-11Rα2 in the hypothalamus ARC in the development of depression, and presents it as a potential novel target for depression treatment.

Corrigendum to "Establishment and verification of the first prognostic nomograms in locally advanced thyroid cancer based on the analysis of clinical and follow-up information on 2396 patients" [Heliyon 10(3), January 2024, e24798].

[This corrects the article DOI: 10.1016/j.heliyon.2024.e24798.].

Effects of Interleukin-19 overexpression in the medial prefrontal cortex on anxiety-related behaviors, BDNF expression and p38/JNK/ERK pathways.

Anxiety is a prevalent mental illness known for its high incidence, comorbidity, and tendency to recur, posing significant societal and individual burdens. Studies have highlighted Interleukin-19 (IL-19) as having potential relevance in neuropsychiatric disorders. Our previous research revealed that IL-19 overexpression in colonies exacerbated anxiety-related behaviors induced by dextran sodium sulfate/stress. However, the precise role and molecular mechanisms of IL-19 in anxiety regulation remain uncertain. In this study, we initiated an acute restraint stress (ARS)-induced anxious mouse model and identified heightened expression of IL-19 and IL-20Rα in the medial prefrontal cortex (mPFC) of ARS mice. Notably, IL-19 and IL-20Rα were predominantly present in the excitatory pyramidal neurons of the mPFC under both basal and ARS conditions. Utilizing the adeno-associated virus (AAV) strategy, we demonstrated that IL-19 overexpression in the mPFC induced anxiety-related behaviors and elevated stress susceptibility. Additionally, we observed decreased protein levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the mPFC of IL-19 overexpression mice, accompanied by reduced phosphorylation of in the p38, JNK, and Erk signaling pathways. These findings emphasize the role of IL-19 in modulating anxiety-related behaviors within the mPFC and suggest its potential as a pathological gene and therapeutic target for anxiety.

Establishment and verification of the first prognostic nomograms in locally advanced thyroid cancer based on the analysis of clinical and follow-up information on 2396 patients.

Background and objectives: The purpose of this research was to develop and validate the first prognostic nomograms for 3-, 5-, and 10-year cancer-specific survival (CSS) and overall survival (OS) in patients diagnosed with locally advanced thyroid cancer (LATC) by evaluating independent predictors of prognosis in a population of LATC patients. Methods: Demographics, clinicopathologic characteristics, treatment, and follow-up of 2396 LATC patients in the surveillance, epidemiology, and end results database from 2004 to 2015 were retrospectively analyzed and compared with patients with LATC according to staging. We randomized all LATC patients into training and validation groups in a 7:3 ratio. Cox regression analyses helped us to derive independent prognostic factors for LATC patients. According to these results, we established and validated the first prognostic nomograms and risk stratification. Results: In our research, the clinical information of LATC patients was compared and significant differences were found in the relevant variables including CSS and OS (P < 0.05), with CSS of 82.0 % and 49.0 %, and OS of 70.6 % and 40.0 %, respectively. Cox regression analyses showed that age at diagnosis, tumor diameter, presence of DM, extrathyroidal extension sites, histological type, thyroidectomy scope, radiotherapy status, and chronological sequence of radiotherapy and surgery were observably correlated with CSS in LATC patients, and in addition to the above factors, gender, marital status, and chemotherapy status were also observably correlated with OS in LATC patients. The prognostic predictive power of the above factors is visualized by the Kaplan-Meier survival curve. The concordance index of nomograms for CSS and OS were 0.933, 0.925, and 0.926 (CSS), 0.918, 0.909, and 0.906 (OS), respectively, and the time-dependent receiver operating characteristic curve, area under curve, calibration curve and decision curve analysis curve indicate that the nomograms have good discriminatory ability, accuracy and clinical applicability in both the training and validation groups. Conclusions: In these findings, we drawed a conclusion that there were significant differences in clinical information between patients with T4a and T4b LATC, and we established and validated the first prognostic nomograms and risk stratification of CSS and OS for LATC patients at 3, 5, and 10 years, which will help clinicians to individualize their postoperative treatment and individualized follow-up.

Blockade of V-domain immunoglobulin suppressor of T-cell activation reprograms tumour-associated macrophages and improves efficacy of PD-1 inhibitor in gastric cancer.

BACKGROUND AND AIMS: In gastric cancer, the response rate of programmed cell death protein-1 (PD-1) inhibitor is far from satisfactory, indicating additional nonredundant pathways might hamper antitumour immunity. V-domain immunoglobulin suppressor of T-cell activation (VISTA) has been reported in several malignancies as a novel immune-checkpoint. Nevertheless, the role of VISTA in gastric cancer still remains obscure. Our purpose is to explore the clinical significance and potential mechanism of VISTA in affecting gastric cancer patients' survival and immunotherapeutic responsiveness. METHODS: Our study recruited eight independent cohorts with a total of 1403 gastric cancer patients. Immunohistochemistry, multiplex immunofluorescence, flow cytometry or intracellular flow cytometry, quantitative polymerase chain reaction, western blotting, fluorescence-activated cell sorting, magnetic-activated cell sorting, smart-seq2, in vitro cell co-culture and ex vivo tumour inhibition assays were applied to investigate the clinical significance and potential mechanism of VISTA in gastric cancer. RESULTS: VISTA was predominantly expressed on tumour-associated macrophages (TAMs), and indicated poor clinical outcomes and inferior immunotherapeutic responsiveness. VISTA+ TAMs showed a mixed phenotype. Co-culture of TAMs and CD8+ T cells indicated that VISTA+ TAMs attenuated effective function of CD8+ T cells. Blockade of VISTA reprogrammed TAMs to a proinflammatory phenotype, reactivated CD8+ T cells and promoted apoptosis of tumour cells. Moreover, blockade of VISTA could also enhance the efficacy of PD-1 inhibitor, suggesting that blockade of VISTA might synergise with PD-1 inhibitor in gastric cancer. CONCLUSIONS: Our data revealed that VISTA was an immune-checkpoint associated with immunotherapeutic resistance. Blockade of VISTA reprogrammed TAMs, promoted T-cell-mediated antitumour immunity, and enhanced efficacy of PD-1 inhibitor, which might have implications in the treatment of gastric cancer.

Genome-Wide Identification and Analysis of the Plant Cysteine Oxidase (PCO) Gene Family in Brassica napus and Its Role in Abiotic Stress Response.

Plant Cysteine Oxidase (PCO) is a plant O2-sensing enzyme catalyzing the oxidation of cysteine to Cys-sulfinic acid at the N-termini of target proteins. To better understand the Brassica napus PCO gene family, PCO genes in B. napus and related species were analyzed. In this study, 20, 7 and 8 PCO genes were identified in Brassica napus, Brassica rapa and Brassica oleracea, respectively. According to phylogenetic analysis, the PCOs were divided into five groups: PCO1, PCO2, PCO3, PCO4 and PCO5. Gene organization and motif distribution analysis suggested that the PCO gene family was relatively conserved during evolution. According to the public expression data, PCO genes were expressed in different tissues at different developmental stages. Moreover, qRT-PCR data showed that most of the Bna/Bra/BoPCO5 members were expressed in leaves, roots, flowers and siliques, suggesting an important role in both vegetative and reproductive development. Expression of BnaPCO was induced by various abiotic stress, especially waterlogging stress, which was consistent with the result of cis-element analysis. In this study, the PCO gene family of Brassicaceae was analyzed for the first time, which contributes to a comprehensive understanding of the origin and evolution of PCO genes in Brassicaceae and the function of BnaPCO in abiotic stress responses.

The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment.

Cancer, as one of the leading causes of death worldwide, has challenged current chemotherapy drugs. Considering that treatments are expensive, alongside the resistance of tumor cells to anticancer drugs, the development of alternative medicines is necessary. Anemarrhena asphodeloides Bunge, a recognized and well-known medicinal plant for more than two thousand years, has demonstrated its effectiveness against cancer. Timosaponin-AIII (TSAIII), as a bioactive steroid saponin isolated from A. asphodeloides, has shown multiple pharmacological activities and has been developed as an anticancer agent. However, the molecular mechanisms of TSAIII in protecting against cancer development are still unclear. In this review article, we provide a comprehensive discussion on the anticancer effects of TSAIII, including proliferation inhibition, cell cycle arrest, apoptosis induction, autophagy mediation, migration and invasion suppression, anti-angiogenesis, anti-inflammation, and antioxidant effects. The pharmacokinetic profiles of TSAII are also discussed. TSAIII exhibits efficacy against cancer development. However, hydrophobicity and low bioavailability may limit the application of TSAIII. Effective delivery systems, particularly those with tissue/cell-targeted properties, can also significantly improve the anticancer effects of TSAIII.

Prediction and screening of circRNA in triple-negative breast cancer.

OBJECTIVE: The purpose of this investigation was to study the expression profile and potential function of circular RNA (circRNA) and long noncoding RNA (lncRNA) in triple-negative breast cancer (TNBC). METHODS: RNA sequencing technology was used to detect differentially expressed circRNAs and lncRNAs between TNBC tissues and the adjacent tissue. The potential functions of these different RNAs were analyzed by GO and KEGG enrichment analysis by bioinformatics tools. We also selected and analyzed these key circRNAs and lncRNAs to verify their important functions in TNBC. RESULTS: A total of 139 differentially expressed circRNAs and 1001 lncRNAs were obtained. The co-expression analysis showed that the hub lncRNAs (OIP5-AS1, DRAIC) were associated with several tumors and mainly enriched in tumor metastasis. We also screened 5 circRNA-hosting genes (NTRK2, FNTA, BAPGEF2, MGST2, ADH1B) that were associated with the brain-derived neurotrophic factor (BDNF) receptor signaling pathway and cerebral cortex development, as well as AMPK and TGF-ß signaling pathway. CONCLUSION: We identified a large number of differentially expressed circRNAs and lncRNAs, which provide useful insight in understanding TNBC carcinogenesis.

Intratumoral PD-1+CD8+ T cells associate poor clinical outcomes and adjuvant chemotherapeutic benefit in gastric cancer.

BACKGROUND: Although PD-1 has been reported to be a marker of T-cell exhaustion in several malignancies, the biological role of PD-1+CD8+ T cells in gastric cancer (GC) remains unclear. Herein, we aimed to investigate the role of PD-1+CD8+ T cells in the tumour microenvironment and its clinical significance in GC. DESIGNS: This study included 441 tumour microarray specimens and 60 Flow cytometry specimens of GC patients from Zhongshan Hospital, and 250 GC patients from the Asian Cancer Research Group. RESULTS: Here, we demonstrated that PD-1+CD8+ T cells functioned as an independent adverse prognosticator in GC. In addition, an abundance of intratumoral PD-1+CD8+ T cells indicated worse chemotherapeutic responsiveness to fluorouracil in Stage III GC patients. Mechanistically, PD-1+CD8+ T cell high infiltration indicated an exhausted phenotype of global CD8+ T cells in GC tissues, which was characterised by elevated immune checkpoint expression including CTLA-4 and TIM-3, whereas decreased expression of perforin. Furthermore, PD-1+CD8+ T cell high-infiltration patients with Stage III GC held elevated activity of several therapeutic signal pathways. CONCLUSIONS: Our study highlighted that PD-1+CD8+ T cell abundance predicts inferior prognosis in GC, and may serve as a novel predictive biomarker to guide therapeutic option.

Inhibition of the PINK1-Parkin Pathway Enhances the Lethality of Sorafenib and Regorafenib in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies and the main cause of cancer-related deaths. The multitarget tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib are systemic therapeutic drugs approved for the treatment of HCC. Here, we found that sorafenib and regorafenib injured mitochondria by inducing mitochondrial Ca2+ (mtCa2+) overload and mitochondrial permeability transition pore (mPTP) opening, resulting in mitochondria-mediated cell death, which was alleviated by cyclosporin A (CsA), an inhibitor of mPTP. Meanwhile, mPTP opening caused PINK1 accumulation on damaged mitochondria, which recruited Parkin to mitochondria to induce mitophagy. Inhibition of autophagy by the lysosomal inhibitor chloroquine (CQ) or inhibition of mitochondrial fission by mdivi-1 aggravated sorafenib- and regorafenib-induced cell death. Moreover, knockdown of PINK1 also promotes sorafenib- and regorafenib-induced cell death. An in vivo study showed that sorafenib and regorafenib inhibited HepG2 cell growth more effectively in PINK1 knockdown cells than in shNTC cells in null mice. Thus, our data demonstrate that PINK1-Parkin-mediated mitophagy alleviates sorafenib and regorafenib antitumor effects in vitro and in vivo.

Intratumoral IL-1R1 expression delineates a distinctive molecular subset with therapeutic resistance in patients with gastric cancer.

BACKGROUND: With the essential role of interleukin-1 signaling in cancer-related inflammation, IL-1R1, the main receptor for both IL-1α and IL-1ß, demonstrated therapeutic potential in several types of cancer, which has been put into clinical trials. However, the expression profile and critical role of IL-1R1 in gastric cancer (GC) remain obscure. This study aimed to investigate the prognostic significance of IL-1R1 expression and its predictive value for chemotherapy and immunotherapy in GC. METHODS: The study enrolled three cohorts, consisting of 409 tumor microarray specimens of GC patients from Zhongshan Hospital, 341 transcriptional data from The Cancer Genome Atlas, and 45 transcriptional data from patients treated with pembrolizumab. IL-1R1 mRNA expression was directly acquired from public datasets, and we also detected IL-1R1 protein expression on tumor microarray by immunohistochemistry. Finally, the associations of IL-1R1 expression with clinical outcomes, immune contexture, and genomic features were analyzed. RESULTS: High IL-1R1 expression predicted poor prognosis and inferior responsiveness to both 5-fluorouracil-based adjuvant chemotherapy (ACT) and immune checkpoint blockade (ICB). IL-1R1 fostered an immunosuppressive microenvironment characterized by upregulated M2 macrophages and exhausted CD8+ T cells infiltration. Moreover, the expression of IL-1R1 was intrinsically linked to genomic alterations associated with targeted therapies in GC. CONCLUSIONS: IL-1R1 served as an independent prognosticator and predictive biomarker for ACT and ICB in GC. Furthermore, IL-1R1 antagonists could be a novel agent alone or combined with current therapeutic strategies in GC.

TIM3+ cells in gastric cancer: clinical correlates and association with immune context.

BACKGROUND: T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a crucial immune checkpoint and is considered as an emerging target for cancer treatment. However, the clinical significance and immune-related role of TIM3+ cells in gastric cancer remain unknown. This study aimed to investigate the clinical significance of tumour-infiltrating TIM3+ cells and their association with immune contexture in gastric cancer. METHODS: This study enrolled three cohorts, including 436 tumour tissue microarray specimens and 58 fresh tumour tissues of gastric cancer patients from Zhongshan Hospital, and 330 transcriptional data from The Cancer Genome Atlas. TIM3+ cells and their association with CD8+ T cells were evaluated by immunohistochemistry and flow cytometry analyses. Kaplan-Meier curves, Cox model and interaction test were performed to assess clinical outcomes. RESULTS: Tumour-infiltrating TIM3+ cells' high subgroups experienced poorer overall survival and disease-free survival and predicted inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. TIM3 indicated CD8+ T cell dysfunction, which impeded chemotherapeutic responsiveness. Besides, HAVCR2 messenger RNA expression was associated with specific molecular characteristics. CONCLUSIONS: The abundance of tumour-infiltrating TIM3+ cells could identify an immunoevasive subtype gastric cancer with CD8+ T cell dysfunction, suggesting that TIM3 might serve as a promising target for immunotherapy 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.

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.

Immune inactivation by APOBEC3B enrichment predicts response to chemotherapy and survival in gastric cancer.

Apolipoprotein B mRNA editing enzyme catalytic polypeptide 3B (APOBEC3B) plays an important role in tumor mutagenesis. However, its clinical significance in gastric cancer (GC) remains largely unknown. We enrolled a total of 482 GC patients from Zhongshan Hospital, Fudan University for immunohistochemistry (IHC) staining to evaluate the prognostic and predictive values of APOBEC3B. Genomic and phenotypic datasets from the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) cohort were downloaded for external validation and complementary bioinformatic analysis. Fresh specimens of additional 60 patients from Zhongshan Hospital, Fudan University were collected to detect CD8+ T cell phenotype with flow cytometry (FCM). The high expression of APOBEC3B indicated inferior overall survival (OS, P < .001 and P = .003) and disease-free survival (DFS, P < .001 and P < .001), yet superior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) in TNM stage II patients. The tumor microenvironment (TME) of APOBEC3B-enriched tumors was characterized by reduced infiltration of tumor reactive CD8+ T cells expressing both effector molecules and immune checkpoints. APOBEC3B high CD8+ T cell high GC patients were most likely to benefit from ACT and PD-1 blockade. Our study demonstrates that APOBEC3B was an independent prognostic and predictive factor in GC. The potential interplay between APOBEC3B and CD8+ T cells merited further investigations.

Impact of intratumoural CD73 expression on prognosis and therapeutic response in patients with gastric cancer.

AIM: CD73 overexpression has been reported in several malignancies and is considered to be a novel immune checkpoint. However, the role and significance of CD73 in gastric cancer (GC) still remain obscure. We aim to investigate the role of CD73 expression in predicting prognosis, shaping immune contexture and guiding therapeutic strategy in GC. METHODS: The study enrolled four independent cohorts with a total of 902 patients with GC. CD73 expression and immune contexture were examined by immunohistochemistry, single-sample gene set enrichment analysis and flow cytometry. Clinical outcomes of patient subgroups were evaluated using the Kaplan-Meier curves and Cox proportional hazard analysis. All statistical tests were two-sided. RESULTS: CD73 was identified as an independent adverse prognostic factor for survival in GC. CD73high tumours showed a specific microenvironment with more CD8+ T cell infiltration, but these CD8+ T cells displayed a dysfunctional phenotype. Furthermore, the CD73 (NT5E) mRNA level was associated with the Cancer Genome Atlas molecular subtypes, and NT5E high tumours showed significant fibroblast growth factor receptor 2 activation and vascular endothelial growth factor and receptor enrichment. In addition, CD73high tumours indicated better chemotherapeutic responsiveness to fluorouracil yet a worse objective response rate to pembrolizumab in GC. CONCLUSIONS: High CD73 expression indicated an immunoevasive contexture with CD8+ T cell dysfunction and represented an independent predictor for adverse clinical outcomes. As a potential immunotherapeutic target, CD73 could potentially be a novel biomarker for adjuvant chemotherapy, targeted therapies and immunotherapy. The crucial role of CD73 in the therapeutic landscape of GC needs further validation retrospectively and prospectively.

Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer.

Studies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein-Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.

Poor clinical outcomes and immunoevasive contexture in CXCL13+CD8+ T cells enriched gastric cancer patients.

As an adverse survival prognosticator, chemokine (C-X-C motif) ligand 13 (CXCL13) has been studied in several types of malignancies. The secretion and physiological roles of CXCL13 in follicular helper T cells (TFH) cells have been well described, while the clinical significance of CD8+ tumor-infiltrating lymphocytes (TILs)-associated CXCL13 remains unknown. This study aims to investigate the clinical significance of CXCL13+CD8+ T cells in survival and chemotherapeutic responsiveness prediction in gastric cancer. In this study, 440 patients enrolled from Zhongshan Hospital with tumor microarray (TMA) specimens were randomly divided into testing set (n = 220) and validation set (n = 220) for analysis. CXCL13+CD8+ T cells were detected by multicolor immunohistochemistry. Fresh tumor tissue samples from another 60 gastric cancer patients were collected to detect CXCL13+CD8+ T cells functional status by flow cytometry (FCM). We found that high intratumoral CXCL13+CD8+ T cells infiltration predicted poor overall survival and inferior chemotherapeutic responsiveness in gastric cancer. CXCL13+CD8+T cells were associated with immunoevasive contexture with increased regulatory T (Treg) cells and dysfunctional cytotoxic T lymphocytes (CTLs). Moreover, the combinational analysis of CXCL13+CD8+ T cells and CD8+ T cells infiltration stratified patients into distinct risk groups with different clinical outcomes and chemotherapeutic responsiveness. Conclusively, intratumoral CXCL13+CD8+ T cells infiltration could be an independent prognostic and predictive marker for gastric cancer patients. CXCL13+CD8+ T cells represented an exhausted CD8+ T cell subset, and might be a potential immunotherapeutic target in gastric cancer.