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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. The prognostic value of tumor infiltrating lymphocytes in gastric cancer remains controversial. Here the authors show a consistent association between higher density of intratumoral CXCR5+CD8+ T cells and longer overall survival in four different cohorts of patients with gastric cancer.

BackgroundAccumulation of basophils has been reported in several malignancies. In gastric cancer, the relation between tumor-infiltrating basophils and patient overall survival and chemotherapeutic responsiveness still remains obscure.ObjectiveWe aimed to investigate the postoperative prognostic and predictive significance of basophils to survival outcomes and chemotherapeutic responsiveness in resectable gastric cancer.MethodsThe study enrolled two independent patient data sets with 448 gastric cancer patients overall. Basophils were evaluated with the use of immunohistochemistry (IHC) staining, and the correlation with clinicopathological characteristics, survival outcomes, and responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) were investigated. Additionally, IHC was applied to characterize immune contexture in gastric cancer.ResultsIn either the discovery or validation data sets, accumulated basophils indicated poorer prognosis, and tumor-infiltrating basophils were identified as an independent adverse prognostic factor by multivariate analysis. Furthermore, tumor-infiltrating basophils determined significantly inferior therapeutic responsiveness to fluorouracil-based ACT in patients with stage III tumors. In addition, the abundance of basophils was correlated with an immunoevasive contexture characterized by M2-polarized macrophage infiltration. Moreover, our findings indicated elevated interleukin-4 expression but decreased interferon-γ expression in the high-basophils subgroup.ConclusionsTumor-infiltrating basophils in gastric cancer were identified as an independent adverse prognosticator, and also predicted inferior chemotherapeutic responsiveness, which identified those patients in need of much more individualized postoperative adjuvant therapy and more stringent follow-up. Furthermore, the infiltration of basophils was associated with immunoevasive tumor microenvironment, which might be a potential immunotherapeutic target for gastric cancer.

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.

BackgroundT 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.MethodsThis 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.ResultsTumour-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.ConclusionsThe 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.

Chromatin remodelers are commonly altered in human cancer. The mutation of AT‐rich interactive domain 1A (ARID1A) in gastric cancer (GC), a component of the SWI/SNF chromatin remodeling complex, was proven associated with treatment response in our previous study. However, ARID1A loss of function was caused not only by mutations but also copy number deletions. The clinicopathologic, genomic, and immunophenotypic correlates of ARID1A loss is largely uncharacterized in GC. Here, 819 patients with clinicopathological information and sequencing data or formalin‐fixed paraffin‐embedded tissues from four cohorts, Zhongshan Hospital (ZSHS) cohort (n = 375), The Cancer Genome Atlas (TCGA) cohort (n = 371), Samsung Medical Center (SMC) cohort (n = 53), and ZSHS immunotherapy cohort (n = 20), were enrolled. ARID1A loss was defined by genome sequencing or deficient ARID1A expression by immunohistochemistry. We found that ARID1A mutation and copy number deletion were enriched in GC with microsatellite instability (MSI) and chromosomal‐instability (CIN), respectively. In the TCGA and ZSHS cohorts, only CIN GC with ARID1A loss could benefit from fluorouracil‐based adjuvant chemotherapy. In the SMC and ZSHS immunotherapy cohorts, ARID1A loss exhibited a tendency of superior responsiveness and indicated favorable overall survival after anti‐PD‐1 immunotherapy. ARID1A‐loss tumors demonstrated elevated mutation burden, neoantigen load, and interferon gamma pathway activation. Moreover, in CIN GC, ARID1A loss was correlated with higher homologous recombination deficiency. ARID1A loss defines a distinct subtype of GC characterized by high levels of genome instability, neoantigen formation, and immune activation. These tumors show sensitivity to both chemotherapy and anti‐PD‐1 immunotherapy. This study provides valuable insights for precision treatment strategies in GC. Our data indicate that ARID1A loss predicted superior benefit from adjuvant chemotherapy (ACT) and anti‐PD‐1 immunotherapy in gastric cancer (GC), especially in chromosomal instability (CIN) subtype, while in non‐CIN subtype, we did not observe any survival benefit from ACT regardless of ARID1A status. ARID1A‐loss GC is associated with elevated mutation burden, neoantigen load, homologous recombination deficiency, and interferon gamma pathway activation. This study may help clinicians stratify patients according to ARID1A status and develop personalized treatment for each molecular subtype in future.

CD96 was identified as a novel immune checkpoint. However, the role of CD96 in the gastric cancer (GC) microenvironment remains fragmentary. This study aimed to probe the clinical significance of CD96 to predict prognosis and therapeutic responsiveness, and to reveal the immune contexture and genomic features correlated to CD96 in GC patients. We enrolled 496 tumor microarray specimens of GC patients from Zhongshan Hospital (ZSHS) for immunohistochemical analyses. Four hundred and twelve GC patients from the Cancer Genome Atlas (TCGA) and 61 GC patients treated with pembrolizumab from ERP107734 published in the European Nucleotide Archive (ENA) were gathered for further analysis of the association between CD96+ cell infiltration and immune contexture, molecular characteristics, and genomic features by CIBERSORT and gene set enrichment analysis. Clinical outcomes were analyzed by Kaplan–Meier curves, the Cox model, interaction testing, and receiver operating characteristic analysis. High CD96+ cell infiltration predicted poor prognosis and inferior survival benefits from fluorouracil‐based adjuvant chemotherapy in the ZSHS cohort whereas superior therapeutic responsiveness to pembrolizumab was shown in the ENA cohort. CD96‐enriched tumors showed an immunosuppressive tumor microenvironment featured by exhausted CD8+ T‐cell infiltration in both the ZSHS and TCGA cohorts. Moreover, in silico analysis for the TCGA cohort revealed that several biomarker‐targeted pathways displayed significantly elevated enrichment levels in the CD96 high subgroup. This study elucidated that CD96 might drive an immunosuppressive contexture with CD8+ T‐cell exhaustion and represent an independent adverse prognosticator in GC. CD96 could potentially be a novel biomarker for precision medicine of adjuvant chemotherapy, immunotherapy, and targeted therapies in GC. CD96+ cells infiltration represented an independent adverse prognosticator and could predict prognosis of adjuvant chemotherapy and therapeutic responsiveness to PD‐1 inhibitor. Immunosuppression by CD96 level was characterized by exhausted CD8+ T cells.

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-β1 (TGF-β1) 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.

BackgroundFoxp3+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.MethodsWe 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.ResultsHigh 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.ConclusionsWe 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 statementsClinical 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.

ObjectiveImmunotherapy has not yielded satisfactory therapeutic responses in gastric cancer (GC). However, targeting myeloid checkpoints holds promise for expanding the potential of immunotherapy. This study aims to evaluate the critical role of Siglec-10+ tumor-associated macrophages (TAMs) in regulating antitumor immunity and to explore the potential of the myeloid checkpoint Siglec-10 as an interventional target.DesignSiglec-10+ TAMs were assessed based on immunohistochemistry on tumor microarrays and RNA-sequencing data. Flow cytometry, RNA sequencing, and single-cell RNA-sequencing analysis were employed to characterize the phenotypic and transcriptional features of Siglec-10+ TAMs and their impact on CD8+ T cell-mediated antitumor immunity. The effectiveness of Siglec-10 blockade, either alone or in combination with anti-programmed cell death 1 (PD-1), was evaluated using an ex vivo GC tumor fragment platform based on fresh tumor tissues.ResultsSiglec-10 was predominantly expressed on TAMs in GC, and associated with tumor progression. In Zhongshan Hospital cohort, Siglec-10+ TAMs predicted unfavorable prognosis (n=446, p<0.001) and resistance to adjuvant chemotherapy (n=331, p<0.001), which were further validated in exogenous cohorts. In the Samsung Medical Center cohort, Siglec-10+ TAMs demonstrated inferior response to pembrolizumab in GC (n=45, p=0.008). Furthermore, Siglec-10+ TAMs exhibited an immunosuppressive phenotype and hindered T cell-mediated antitumor immune response. Finally, blocking Siglec-10 reinvigorated the antitumor immune response and synergistically enhances anti-PD-1 immunotherapy in an ex vivo GC tumor fragment platform.ConclusionsIn GC, the myeloid checkpoint Siglec-10 contributes to the regulation of immunosuppressive property of TAMs and promotes the depletion of CD8+ T cells, ultimately facilitating immune evasion. Targeting Siglec-10 represents a potential strategy for immunotherapy in GC.