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.

/pdf/the-efficacy-of-cancer-immunotherapies-is-compromised-by-13yodxg1.pdf

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

High expression of programmed death ligand‐1 (PD‐L1) has been related to good response to immunotherapy patients with gastric cancer (GC). However, the influence of Helicobacter pylori (HP) infection on PD‐L1 expression in GC remains unknown. A meta‐analysis was performed to evaluate the association between HP infection and PD‐L1 expression in GC.

Helicobacter pylori infection and PD‐L1 expression in gastric cancer: A meta‐analysis

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.

Dongmei Gu

Papers

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