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Abstract Objectives CD4+ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor‐infiltrating CD4+ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown. Methods A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD‐1 on CD4+ T cells in the different samples was analysed by flow cytometry. GC‐infiltrating CD4+ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC‐infiltrating T cells was investigated by inhibiting CD39 enzymatic activity. Results In comparison with CD4+ T cells from the non‐tumor tissues, significantly more GC‐infiltrating CD4+ T cells expressed CD39. Most GC‐infiltrating CD39+CD4+ T cells exhibited CD45RA−CCR7− effector–memory phenotype expressing more exhaustion‐associated inhibitory molecules and transcription factors and produced less TNF‐α, IFN‐γ and cytolytic molecules than their CD39−CD4+ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF‐α and IFN‐γ production. Finally, increased percentages of GC‐infiltrating CD39+CD4+ T cells were positively associated with disease progression and patients' poorer overall survival. Conclusion Our study demonstrates that CD39 expression defines GC‐infiltrating CD4+ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.

Helicobacter pylori (H. pylori) infection is associated with various gastric and extra-gastric diseases. Importantly, this infection is the strongest known risk factor for gastric cancer (GC). H. pylori eradication can effectively prevent H. pylori infection-associated diseases in H. pylori-positive patients, including children and elderly subjects. However, a limited selection of antibiotics, a higher reinfection rate, and certain spontaneous clearance rates, to some extent, restrict the choice of H. pylori treatments in pediatrics. In addition, it is imperative to perform an accurate diagnosis of H. pylori infection in children by determining the presence of the H. pylori infection and the underlying cause of symptoms. In elderly patients, poor tolerance to drugs and higher sensitivity to adverse effects are major concerns during H. pylori therapy. Recent studies have demonstrated that H. pylori eradication could significantly lower the GC risk in the elderly population. The benefit and risk of H. pylori eradication in elderly patients should be comprehensively considered and balanced. If available, susceptibility-based tailored therapies may be preferable in eradicating H. pylori. In addition, to increase the eradication rate and reduce adverse effects, new therapeutic strategies (e.g., probiotic supplementation, berberine supplementation, dual therapy) for H. pylori infection are being extensively investigated. The impact of H. pylori eradication with antibiotics on the microbiota in children has been explored, but further high-quality studies are crucial to delineate the extent of H. pylori eradication affecting the microbial community in children. In this review, we summarize the current understanding of H. pylori diagnosis and treatment in children and the elderly population and aim to provide insights into the efficient management and treatment implementation in these populations. Keywords: Children, Elderly, Helicobacter pylori, Diagnosis, Treatment

Abstract Rationale Neutrophils constitute massive cellular constituents in inflammatory human gastric cancer (GC) tissues, but their roles in pathogenesis of inflammatory T helper (Th) subsets are still unknown. Methods Flow cytometry analysis and immunohistochemistry were used to analyze the responses and phenotypes of neutrophils in different samples from 51 patients with GC. Kaplan‐Meier plots and Multivariate analysis for the survival of patients were used by log‐rank tests and Cox proportional hazards models. Neutrophils and CD4+ T cells were purified and cultured for ex vivo, in vitro and in vivo regulation and function assays. Results GC patients exhibited increased tumoral neutrophil infiltration with GC progression and poor patient prognosis. Intratumoral neutrophils accumulated in GC tumors via CXCL6/CXCL8‐CXCR1‐mediated chemotaxis, and expressed activated molecule CD54 and co‐signaling molecule B7‐H2. Neutrophils induced by tumors strongly expressed CD54 and B7‐H2 in both dose‐ and time‐dependent manners, and a close correlation was obtained between the expressions of CD54 and B7‐H2 on intratumoral neutrophils. Tumor‐derived tumor necrosis factor‐α (TNF‐α) promoted neutrophil activation and neutrophil B7‐H2 expression through ERK‐NF‐κB pathway, and a significant correlation was found between the levels of TNF‐α and CD54+ or B7‐H2+ neutrophils in tumor tissues. Tumor‐infiltrating and tumor‐conditioned neutrophils effectively induced IL‐17A‐producing Th subset polarization through a B7‐H2‐dependent manner ex vivo and these polarized IL‐17A‐producing Th cells exerted protumorigenic roles by promoting GC tumor cell proliferation via inflammatory molecule IL‐17A in vitro, which promoted the progression of human GC in vivo; these effects could be reversed when IL‐17A is blocked. Moreover, increased B7‐H2+ neutrophils and IL‐17A in tumors were closely related to advanced GC progression and predicted poor patient survival. Conclusion We illuminate novel underlying mechanisms that TNF‐α‐activated neutrophils link B7‐H2 to protumorigenic IL‐17A‐producing Th subset polarization in human GC. Blocking this pathological TNF‐α‐B7‐H2‐IL‐17A pathway may be useful therapeutic strategies for treating GC.

Natural killer (NK) cell activity is influenced by a complex integration of signaling pathways activated downstream of both activating and inhibitory surface receptors. The tumor microenvironment can suppress NK cell activity, and there is a great clinical interest in understanding whether modulating tumor-mediated NK cell suppression and/or boosting preexisting NK cell numbers in cancer patients is therapeutically viable. To this light, we characterized the surface receptor phenotypes of peripheral blood NK cells and examined their clinical relevance to human gastric cancer (GC). We found that the proportion of peripheral blood NK cells which expressed the activating receptors NKp30, NKp46, NKG2D, and DNAM-1 was significantly decreased in GC patients compared to healthy donors, and that this decrease was positively associated with tumor progression. At the same time, plasma TGF-β1 concentrations were significantly increased in GC patients and negatively correlated with the proportion of NKp30, NKp46, NKG2D, and DNAM-1 expressing NK cells. Furthermore, TGF-β1 significantly downregulated the expression of NKp30, NKp46, NKG2D, and DNAM-1 on NK cells in vitro, and the addition of galunisertib, an inhibitor of the TGF-β receptor subunit I, reversed this downregulation. Altogether, our data suggest that the decreased expression of activating receptors NKp30, NKp46, NKG2D, and DNAM-1 on peripheral blood NK cells is positively associated with GC progression, and that TGF-β1-mediated NK cell suppression may be a therapeutically targetable characteristic of GC.