Gastric cancer is a global health issue, with over 1 million newly diagnosed cases globally each year (1). Despite the descended morbidity and mortality of this malignancy during the last five years, it is still the third major cause of cancer-related deaths (2). The prognosis of advanced gastric cancer is undesirable with a five-year survival rate of less than 30%. Platinum-fluoropyrimidine combination chemotherapy represents the first-line therapeutic option against advanced patients (1). However, patients usually have a low complete response rate to chemotherapy, with substantial toxicity. Gastric cancer is diagnosed histologically following endoscopic biopsy as well as staged utilizing computed tomography, endoscopic ultrasound, positron emission tomography, and laparoscopy. Currently, histopathological classification schemes designate gastric cancer as intestinal or diffuse in accordance with the morphology, differentiation, and cohesion of glandular cells. Intestinal gastric cancer is preceded through alterations in the gastric mucosa as the Correa cascade that evolves via inflammatory response, metaplasia, dysplasia, or adenocarcinoma. Diffuse gastric cancer lacks cell adhesion and exhibits a diffuse aggressive growth feature. Recently, comprehensive evaluation of the Cancer Genome Atlas (TCGA) has categorized this malignancy as 4 molecular subtypes: genome stable (GS), microsatellite instability (MSI), EBV infection, as well as chromosomal instability (CIN) (3). Moreover, the Asian Cancer Research Group (ACRG) project offers a new molecular classification, including MSI subtype, microsatellite stable with epithelial to mesenchymal transition (MSS/EMT), MSS/TP53 mutant (MSS/TP53+), and MSS/TP53 wild-type (MSS/TP53-) subtypes (4). In terms of histopathological or molecular classifications, gastric cancer is not an isolated mass of cancerous epithelial cells. In contrast, these tumors present a complex morphology in which tumor cells are surrounded by the tumor microenvironment (TME) (5). The TME contains extracellular matrix (ECM), stromal cells, immune cells, and secreted factors, which present high correlations to gastric cancer progression and therapeutic responses (6). The innate immune cell populations (macrophage, neutrophil, dendritic cell, innate lymphoid cell, myeloid-derived suppressor cell, natural killer cell) as well as adaptive immune cell populations (T cell and B cell) trigger gastric cancer progression within the TME (7). Innate and adaptive immune responses exert critical functions in tumor immune surveillance as well as suppression of tumor progression. Tumor cells inhibit the immune system, and thus evade immune disruption and facilitate tumor growth, and metastases. Tumor immune surveillance is capable of recognizing and eliminating tumor cells. Tumor immune escape permits tumor cells to proliferation and metastases following escaping immune surveillance and thus results in unfavorable clinical outcomes. Numerus factors participate in the process of tumor immune escape, especially Helicobacter pylori (H. pylori) infection.

H. pylori is a gram-negative microaerobic spiral rod-shaped bacteria that colonizes the surface of human stomach mucosa (2). It is a highly invasive microorganism and is one of the reasons for the highest incidence of chronic infections in the world, though more than 80% of infected patients are still asymptomatic (2). At present, several virulence-related genes in the genome of H. pylori have been confirmed, mainly cytotoxin-associated gene A (cagA), vacuum toxin gene A (vacA), induced by contact epithelium (iceA), blood group antigen-binding Adhesin gene (babA), etc. (2). Over 50% of individuals are infected with H. pylori across the globe. Nearly all cases of gastric cancer are linked with H. pylori infection (8). H. pylori eradication is capable of preventing gastric cancer progression and quadruple therapy (bismuth quadruple and concomitant) is the recommended first-line therapeutic option (8). However, antibiotic resistance with a growing prevalence is the main reason for the therapeutic failure of H. pylori. Growing evidence suggests the crucial roles of H. pylori infection in immune evasion mechanisms during gastric cancer progression (8). The persistence of H. pylori infection results in an immunosuppressive microenvironment as well as allows gastric carcinoma cells to evade immune surveillance (8). In this review, we summarize a comprehensive outline of research advances of the molecular mechanisms concerning the crosstalk of H. pylori with components within the TME of gastric cancer, suggesting the crucial roles of H. pylori infection in tumor immune escape.

B and T cells are central mediators of adaptive immunity (33). H. pylori infection deregulates T and B cells to mediate immune escape of gastric epithelial cells (34). Immune score has been exploited for estimating the adaptive immune compositions within the TME. In accordance with immune score, tumors are categorized into four subtypes: hot, altered-excluded, altered-immunosuppressed, as well as cold (35). Hot tumors present the features of enhanced infiltrations of PD-1- or CTLA4-expressing cytotoxic T lymphocytes as well as tumor cells expressing costimulatory molecules that are capable of maintaining T-cell functions (36). Intriguingly, hot tumors present the features of the presence of local inflammatory responses as well as high responses to immunotherapy. T-cell exclusion inside the tumors, triggered by the presence of abnormal vasculature and fibrotic nets, represents a major characteristic of altered-excluded immune tumors. Altered-immunosuppressed tumors present the intermediate infiltrations of exhausted T cells and the increased density of soluble inhibitory factors and immune-suppressive cell populations. Cold tumors present the characteristics of the absence of T-cell infiltrations because the cells or mechanisms underlying T-cell priming or activation are lacking. H. pylori-induced adrenomedullin facilitates IFN-γ-producing T-cell responses within the gastric microenvironment (37). The production of suppressive cytokine IL-10 in H. pylori-infected gastric cancer patients is elevated and thus results in a decreased cytotoxic anti-tumor T-cell response in the gastric mucosa, thereby contributing to gastric carcinogenesis (38). H. pylori VacA targets myeloid cells in the gastric mucosa and thus creates a tolerogenic environment that promotes regulatory T-cell (Treg) differentiation and suppresses effector T-cell priming and functionality (39).

Figure 1 summarizes the crosstalk of H. pylori with innate immune cells within the TME, including TAMs, neutrophils, dendritic cells, MDSCs, and NK cells.

CAFs are a major stromal component that display massive infiltrations within the TME (40). CAFs are mainly distributed around blood vessels or in the fibrous interstitium around tumors, secreting cytokines, ECM components, and related enzyme molecules (41). ECM provides physical support for cells in the TME and plays an important role in cell adhesion and infiltration. ECM deposition can produce dense fibrous interstitium that envelops tumors, which makes tumor tissues more brittle and firmer than normal tissues, thereby forming a physical barrier that hinders immune cell infiltration, and inhibiting anti-tumor drugs from targeting the TME (40). Moreover, the matrix metalloproteinases secreted by CAFs can reshape ECM, release chemokines, growth factors, and pro-angiogenesis factors, and promote the malignant transformation of tumors. With the rapid growth of tumors and vascular alienation, insufficient blood supply often occurs in the tumors and long-term hypoxia (42). Meanwhile, cell metabolism will increase the accumulation of lactose and hydrogen ions to form the acidic TME. The activation of a cascade of signals caused by vascular defects and metabolic disorders promotes the formation of immunosuppressive TME (43). CAF mainly affects TME through four perspectives: tumor cell proliferation and metastases, angiogenesis, ECM remodeling, and immune inhibition. H. pylori can activate gastric fibroblasts into cells possessing CAFs. H. pylori infection increases vascular adhesion molecule 1 (VCAM1) expression in CAFs within the TME through activating the JAK/STAT1 pathway, and CAF-derived VCAM1 interacts with integrin αvβ1/5 in gastric cancer cells to trigger cancer invasion (40). H. pylori infection induces the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway and enhances PGE2 production, leading to the hypermethylation of miR-149 in CAFs as well as the increase in IL-6 secretion. Epigenetic silencing of miR-149 in CAFs mediates the interplay of CAFs with gastric cancer cells within the TME (44).

Epithelial–mesenchymal transition (EMT) process may confer mesenchymal phenotype and characteristics to epithelial cells (45, 46), with the abnormality of epithelial polarization and cell-to-cell junction as well as acquiring mesenchymal and motile phenotypic changes (47). H. pylori infection triggers the EMT of epithelial cell populations in the stomach mucosa. Moreover, this process can result in the appearance of CSC characteristics in gastric cancer. CSCs are a rare cell subset in tumors, which can initiate the progression and spread of tumors to induce distant metastasis. H. pylori infection can unveil CSC-like properties through inducing EMT-like alterations in gastric epithelial cells via CagA (47). Hippo pathway effectors yes-associated protein (YAP) along with transcriptional co-activator with PDZ binding motif (TAZ) mediates gastric carcinoma occurrence or development. TAZ activation responding to H. pylori can result in H. pylori-triggered EMT as well as CSC features. Thus, TAZ up-regulation constitutes a contributor of early conversion during H. pylori-induced gastric cancer initiation (48). Bone marrow-derived MSCs facilitate H. pylori-induced gastric cancer progression via secretion of thrombospondin-2 (49).

H. pylori infection has been considered as a microorganism that is highly effective in triggering inflammatory response within the stomach. Recent research has revealed a synergistic interplay of H. pylori infection with the components within the TME. An in-depth comprehension of how H. pylori and these cell populations interact can provide novel ideas and perspectives in treating gastric cancer and promising biomarkers for early detection. As mentioned, the interactions of H. pylori infection with TAMs, neutrophils, dendritic cells, MDSCs, NK cells, B and T cells, CAFs, and MSCs exert crucial roles in gastric carcinogenesis.

Because H. pylori infection can induce strong immune response in the stomach, the resulting inflammation can facilitate gastric cancer progression. Most studies investigating the influence of H. pylori infection on the mentioned cell populations within the TME have been conducted in vitro. Furthermore, the exact mechanisms underlying the interplay of H. pylori infection with the TME should be addressed, assisting better expounding of the roles of H. pylori infection in gastric carcinogenesis. More biomedical or pharmaceutical regimens specifically targeting H. pylori infection can offer potential treatment methods for gastric cancer prevention.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

This work was funded by Shanxi Provincial Health Commission Project (RK-26); Shanxi Provincial Science and Technology Department Project (2018041056-6); The Second Hospital of Shanxi Medical University Fund Project (201702-2); Research on the current situation and countermeasures of the transformation of scientific and technological achievements in large general hospitals (202104031402141); Research on the implementation of medical alliance management model in public hospitals and primary medical and health service institutions (202104031402138).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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