Helicobacter pylori is closely associated with gastric cancer. During persistent infection, Helicobacter pylori can form a microenvironment in gastric mucosa which facilitates the survival and colony formation of Helicobacter pylori. Tumor stromal cells are involved in this process, including tumor-associated macrophages, mesenchymal stem cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells, and so on. The immune checkpoints are also regulated by Helicobacter pylori infection. Helicobacter pylori virulence factors can also act as immunogens or adjuvants to elicit or enhance immune responses, indicating their potential applications in vaccine development and tumor immunotherapy. This review highlights the effects of Helicobacter pylori on the immune microenvironment and its potential roles in tumor immunotherapy responses.

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Effects of helicobacter pylori on tumor microenvironment and immunotherapy responses

Helicobacter pylori infects the gastric mucosa of a large number of humans. Although asymptomatic in the vast majority of cases, H pylori infection can lead to the development of peptic ulcers gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Using a variety of mechanisms, H pylori locally suppresses the function of the host immune system to establish chronic infection. Systemic immunomodulation has been observed in both clinical and pre-clinical studies, which have demonstrated that H pylori infection is associated with reduced incidence of inflammatory diseases, such as asthma and Crohn’s disease. The introduction of immunotherapies in the arsenal of anti-cancer drugs has revealed a new facet of H pylori-induced immune suppression. In this review, we will describe the intimate interactions between H pylori and its host, and formulate hypothtyeses describing the detrimental impact of H pylori infection on the efficacy of cancer immunotherapies.

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The Efficacy of Cancer Immunotherapies Is Compromised by Helicobacter pylori Infection

The tumor microenvironment and tumor immunity are crucially involved in tumor therapy. Immune checkpoint inhibitors targeting PD‐1/PD‐L1 signal transduction have been widely used in tumor therapy and have shown ideal clinical efficacy. However, some kinds of cancers still do not respond to PD‐1/PD‐L1 blockade therapy effectively, including gastric cancer. The related factors should be explored.

Influence of Helicobacter pylori infection on PD‐1/PD‐L1 blockade therapy needs more attention

Immunotherapy, especially immune checkpoint inhibitors, has been widely used in tumor therapy and have shown ideal clinical efficacy. However, some cancers still do not respond to PD‐1/PD‐L1 blockade therapy effectively. Helicobacter pylori infection might affect the curative effect of immunotherapy while it is rarely reported. We aimed to visualize the research hotspots and trends of H. pylori and immunotherapy using a bibliometric analysis to help understand the future development of basic and clinical research.

Effect of Helicobacter pylori on immunotherapy is gaining more attention

DNA polymerase θ belongs to the A family of DNA polymerases and plays a key role in DNA repair and damage tolerance, including double-strand break repair and DNA translesion synthesis. Pol θ is often overexpressed in cancer cells and promotes their resistance to chemotherapeutic agents. In this review, we discuss unique biochemical properties and structural features of Pol θ, its multiple roles in protection of genome stability and the potential of Pol θ as a target for cancer treatment.

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Multifaceted Nature of DNA Polymerase θ

As a key virulence factor for persistent colonization, urease B subunit (UreB) is considered to be an ideal vaccine antigen against Helicobacter pylori infection. However, the role and molecular mechanisms of UreB involved in immune microenvironment dysregulation still remain largely unknown. In the present study, we evaluated the effects of UreB on macrophage activation and found that UreB induced PD-L1 accumulation on bone marrow-derived macrophages (BMDMs). Co-culture assays further revealed that UreB-induced PD-L1 expression on BMDMs significantly decreased the proliferation and secretion of cytolytic molecules (granzyme B and perforin) of splenic CD8+ T cells isolated from inactivated H. pylori-immunized mice. More importantly, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation techniques, it has been confirmed that myosin heavy chain 9 (Myh9) is a direct membrane receptor for UreB and is required for PD-L1 up-regulation on BMDMs. Molecular studies further demonstrated that the interaction between UreB and Myh9 decreased GCN2 autophosphorylation and enhanced the intracellular pool of amino acids, leading to the up-regulation of S6K phosphorylation, a commonly used marker for monitoring activation of mTORC1 signaling activity. Furthermore, blocking mTORC1 activation with its inhibitor Temsirolimus reversed the UreB-induced PD-L1 up-regulation and the subsequent inhibitory effects of BMDMs on activation of cytotoxic CD8+ T-cell responses. Overall, our data unveil a novel immunosuppressive mechanism of UreB during H. pylori infection, which may provide valuable clues for the optimization of H. pylori vaccine.

Helicobacter urease suppresses cytotoxic CD8+ T-cell responses through activating Myh9-dependent induction of PD-L1.

DNA polymerase (Pol) ν and Pol θ are two specialized A-family DNA polymerases that function in the translesion synthesis of certain DNA lesions. However, the biological functions of human Pols ν and θ in cellular replicative bypass of 8-oxo-7,8-dihydroguanine (8-oxoG), an important carcinogenesis-related biomarker of oxidative DNA damage, remain unclear. Herein, we showed that depletion of Pols ν and θ in human cells could cause an elevated hypersensitivity to oxidative stress induced by hydrogen peroxide. Using next-generation sequencing-based lesion bypass and mutagenesis assay, we further demonstrated that Pols ν and θ had important roles in promoting translesion synthesis of 8-oxoG in human cells. We also found that the depletion of Pol ν, but not Pol θ, caused a substantial reduction in G → T mutation frequency for 8-oxoG. These findings provided novel insights into the involvement of A-family DNA polymerases in oxidative DNA damage response.

Next-Generation Sequencing-Based Analysis of the Roles of DNA Polymerases ν and θ in the Replicative Bypass of 8-Oxo-7,8-dihydroguanine in Human Cells.

Acidic nuclear phosphoprotein 32 family member E (ANP32E) is a histone chaperone that removes H2A.Z from chromatin. ANP32E is implicated in numerous cellular processes, including cell proliferation, apoptosis and cell differentiation. Increasing evidence suggests that dysregulation of ANP32E expression is strongly associated with carcinogenesis. However, the relationship between ANP32E in the development of gastric cancer (GC) is unknown. The present study aimed to explore the potential role of ANP32E in the development of GC using gain-of-function, loss-of-function, CCK-8, colony formation, apoptosis, reverse transcription-quantitative PCR, immunoblotting and luciferase reporter assay. The results of the present study demonstrated that ANP32E expression levels were significantly increased in GC tissues. ANP32E knockdown markedly inhibited GC cell proliferation and colony formation and significantly induced GC cell apoptosis, whereas overexpression of ANP32E significantly induced GC cell malignancy. Furthermore, the results demonstrated that there was a positive association between ANP32E and NUF2 component of NDC80 kinetochore complex (NUF2) expression levels. By assessing NUF2 expression levels, it was demonstrated that ANP32E promoted tumor cell proliferation and inhibited cell apoptosis by increasing NUF2 expression levels in GC cell lines. In conclusion, the present study indicated that ANP32E may function as an efficient oncogene, which promotes tumorigenesis of GC cells by inducing NUF2 expression.

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Xiaowen Zhu

Papers

Helicobacter urease suppresses cytotoxic CD8+ T-cell responses through activating Myh9-dependent induction of PD-L1.

Next-Generation Sequencing-Based Analysis of the Roles of DNA Polymerases ν and θ in the Replicative Bypass of 8-Oxo-7,8-dihydroguanine in Human Cells.

ANP32E contributes to gastric cancer progression via NUF2 upregulation

SIRT1 enhances oxaliplatin resistance in colorectal cancer through microRNA‐20b‐3p/DEPDC1 axis