Dynamic Changes of Host Immune Response during Helicobacter pylori-Induced Gastric Carcinogenesis

Abstract

Helicobacter pylori infection is identified as a primary risk factor for gastric cancer (GC). Chronic inflammation is usually induced by H. pylori infection and accompanied by inherent immune disorders. According to Correa’s model, gastritis could progress to premalignant lesions, such as intestinal metaplasia and dysplasia, and ultimately GC. The interaction of H. pylori with the gastric mucosa leads to the recruitment of immune cells, including dendritic (DC) cells, natural killer (NK) cells, and T and B lymphocytes, and triggers inflammatory response with cytokine production, which results in the pathogenesis of stomach. The balance between inflammation and immunity is important to gastric cancer development. However, the dynamic change of immune response during the transition from normal to metaplasia to dysplasia and GC is largely undefined. In this review, we summarized the involvement of key immune cells during GC progression, aiming to help identify inflection points and associated biomarkers for early GC detection, diagnosis, and therapies.

1. Introduction

The lifetime risk of gastric cancer in patients with Helicobacter pylori infection is 1–5%, depending on ethnicity and environmental factors [1]. Some populations have an increased risk of gastric cancer after H. pylori infection, which can be attributed to genetics, housing status, and dietary habits, such as increased consumption of salty or pickled foods in East Asian populations. According to the global burden of cancer attributable to infections in 2018 [2], chronic tissue damage with necrosis and regeneration carries an increased cancer risk, especially chronic gastritis caused by H. pylori infection. Characteristics of multiple carcinomas suggest that immunologic factors modulate susceptibility to gastric tumors. Nowadays, a significant number of studies have found that H. pylori infection is closely related to the occurrence and development of some gastrointestinal diseases, including chronic active gastritis, peptic ulcer, gastric cancer, and gastric mucosa-associated lymphoid lymphoma (MALT). The pathogenic mechanism of H. pylori infection is very complex; in addition to the damage to the gastric mucosa caused by H. pylori’s own kinetic apparatus, adhesion properties, and various virulence factors and host genetics, there are also inflammatory and immune responses induced by H. pylori infection. During H. pylori infection, several cytokines, such as interferon (IFN) and interleukins (IL), play a crucial role in regulating immune and inflammatory responses. In this paper, we reviewed the immunological mechanisms of immune cells and immune molecules in the pathogenesis of gastric mucosa during H. pylori infections.

2. H. pylori infection associated with T cells

2.1 T helper (Th) cell-mediated gastric mucosal inflammation

CD4⁺ T cells play a critical role in the immune response elicited during H. pylori infection, and Th1 cells undergo the earliest polarized proliferation among them. CD4⁺ T cells have two primary functions: to promote the inflammatory response and antibody production by B cells. Th1 cells secrete IFN-γ and IL-2 to enhance antigen presentation and to promote bactericidal action by macrophages. Th2 cells secrete IL-4, IL-5, and IL-13. These can promote B-cell proliferation and the production of antibodies. We elaborated on the change of immune cells and how these cells act as a protective factor or cause damage to the gastric mucosa after H. pylori infection.

H. pylori can induce Th1 cell response early during acute infection [3]. Additionally, the Th1 cell response was activated by the gastric mucosa dendritic cells in humans [4]. CagY, an H. pylori protein, can drive both B-cell proliferation and T-cell activation in gastric MALT lymphomas [5]. They have upregulated the mRNA expression of Notch1 involved in the differentiation of Th1 cells during H. pylori infection. H. pylori activates the Th1-Th2 response, activating B cells associated with the Th1 response and the Th2-specific antibody IgG1 [6]. Although earlier studies showed a protective factor for Th2 response in protection from H. pylori infection, more new reports suggested that protection from H. pylori is related to the progression of Th1 responses, which are accompanied by the high expression of IFN-γ and IL-12 and elevated IgG2a/IgG1 ratio as well. Formulations containing rCagA promote a Th1 response and induce Th1/Th2 balance through elevating IL-4, IL-10, and TGF-β levels, which were in line with the proliferation of spleen cells [6].

Th17, a newly identified CD4⁺ T-cell subtype expressing IL-17A, IL-17F, IL-21, and the chemokine CCL20, as well as the transcription factor RORγt, is involved in the gastric mucosal inflammatory response to H. pylori infection. Studies proved that the Th17 response could effectively protect against H. pylori infection if mice were immunized with inactive H. pylori [7]. In patients with peptic ulcers infected with different bacterial types of H. pylori, CD4⁺ T cells increased. Increased regulatory T-cell activity can reduce the Th17/IL-17 mediated mucosal immune response in the stomach, while Th17 cut can reduce neutrophil accumulation and decrease inflammation in H. pylori-infected children [8]. A series of cytokines and transcription factors can regulate the differentiation and function of Th17. More detailed research can be found in this influencing review [9].

Th22 cells and IL-22 play a proinflammatory role in infectious disease [10]. After H. pylori infection, IL-22 can inhibit epithelial cell apoptosis and promote epithelial proliferation and regeneration [11], exerting tissue-protective effects regulated by IL-17A [12].

Although H. pylori infection of the gastric mucosa can cause Th cells and the inflammatory factors they secrete to accumulate in large numbers and cause disease, the gastric mucosal tissues continue to be damaged after the eradication of H. pylori.

2.2 Regulatory T-cell mediated gastric mucosal tolerance

Regulatory T cells (Tregs) are characterized by high levels of CD25, low levels of CD127, and inhibitory cytokines (e.g., IL-10 and the transcription factor Foxp3). They are essential in regulating cellular immune response and maintaining autoimmune tolerance. Tregs inhibit antigen-induced immune reactions, and disordered Treg activation induced by microbial antigens may be a mechanism by which H. pylori evades host immune attack. CagA, γ-glutamyl transpeptidase (γGT), vacuolar cytotoxin A (VacA), etc., from H. pylori, triggered the differentiation of tolerogenic dendritic cells (DCs), resulting in a bias of Treg cells toward a Th response. γGT, VacA, and arginase inhibited the proliferation of CD4⁺ and CD8⁺ T cells [13].

Tregs, CD4⁺CD25⁺Foxp3⁺ T cells, are essential in regulating the cellular immune response and maintaining autoimmune tolerance. Tregs negatively regulate the immune response mainly in two ways: one is to inhibit the activation of the target cells directly, and the other is to secrete cytokines, such as TGF-β and IL-10, to inhibit the immune response. In addition, Tregs can hinder the immune response induced by antigens and antibodies, and the abnormal activation of Tregs induced by microbial antigens may be one of the mechanisms by which H. pylori evades host immune attack [14]. The expression levels of CD4⁺ T cells, Foxp3⁺ Treg cells, and TGF-β1 were higher in children infected with H. pylori, and the number of Foxp3⁺ Treg cells and the expression of TGF-β1 inflammatory factors were positively correlated with having H. pylori infection. The results suggest that Treg cells may play an essential role in the persistent infection of gastric mucosa by H. pylori [15]. An increased number of Treg cells increases the chances of H. pylori infection in children. The two immune cells, Treg and Th, are in equilibrium in the normal state of the organism. In contrast, increased secretion of Treg inhibits the Th-mediated inflammatory response when H. pylori infects the organism, which is an essential reason for the involvement of Treg in the pathogenesis of H. pylori infection [16]. Among H. pylori-infected people, a large amount of Treg accumulates in their gastric mucosa when Treg exerts an immunosuppressive function. Researchers found that two conditions are required for this phenomenon to occur. First, chemokines attract Treg to migrate from the bloodstream to the gastric mucosa; second, Treg can express chemokine receptors and some adhesion molecules. It was further found that chemokine receptor 6 (CCR6) expressed by gastric mucosal epithelial cells can combine with its ligand chemokine CCL20 to elicit immune responses, and the immunoreactivity of H. pylori can cause H. pylori to express a large amount of CCL20. At the same time, the virulence factor cagPAI can make H. pylori express a large amount of CCL20. H. pylori’s virulence factor, cagPAI, can cause H. pylori to express CCL20 in large quantities [17].

Although H. pylori establishes an immune-tolerant environment to some degree, proinflammatory signaling molecules can still initiate systemic and local T-cell inflammatory immune responses to damage gastric mucosal tissues. In the research of gastric cancers associated with H. pylori, it would be essential to emphasize the crosstalk of EPHA2 with other RTKs and with different signaling pathways that are well-known driving factors of carcinogenesis and tumor aggressiveness, such as EGFR, MET, and the WNT/β-catenin pathway [18].

2.3 Cytotoxic T-lymphocyte-mediated gastric mucosal inflammation

H. pylori can induce the host CD4⁺ T-cell immune responses to provide protection, but less is known of CD8⁺ T-cell responses. CD8⁺ T cells have long been considered unrelated to the immune response to H. pylori. Still, some studies on the characterization of H. pylori-associated CD4⁺ T cells have also referred to the infiltration of gastric mucosa by CD8⁺ T cells [19]. In H. pylori infection, early mucosal T-cell immune response is dominated by CD8⁺ T cells to control pathogens at the cost of increased tissue inflammation; CD8⁺ T cells are later overtaken by CD4⁺ T cells. H. pylori-induced gastric CD8⁺T cells display a tissue-resident memory (T_RM) phenotype (T⁺_RM phenotype) [20]. A research team infected C57BL/6 mice with the pathogenic CagA-proficient H. pylori strain PMSS1 at different periods and analyzed single-cell suspensions of the gastric mucosa via flow cytometry. Urease subunit B (UreB) is a conserved and critical virulence factor of H. pylori. The peripheral blood mononuclear cells (PBMCs) collected from H. pylori-infected individuals were stimulated with recombinant UreB (rUreB) in vitro to detect specific CD8⁺ T-cell responses after coculturing with rUreB-pulsed autologous human monocyte-derived dendritic cells (hMDCs) [21]. CD8⁺ T cells could play an inflammatory scavenging role and kill bacteria in the absence of CD4⁺ T-cell immunoprotection in mice infected with H. pylori, such as in the case of H. pylori-infected GK1.5 (anti-CD4)-treated mice. H. pylori-infected MHC-II knockout mice (both lacked CD4⁺ T cells) had significant accumulation of CD8⁺ T cells in the gastric mucosa and had severe gastric mucosal injury, suggesting that CD8⁺ T cells may mediate the gastric mucosal inflammatory response [22]. Moreover, the researcher established an animal experimental model of H. pylori-infected pigs by gavage. The histopathology of the gastric mucosa was similar to that of H. pylori-infected humans. The expression of immune molecules such as the marker protein T-bet, CD16, perforin, and granzyme of CD8⁺ cytotoxic T lymphocytes (CTL) was high, which suggests that CTL mediated gastric mucosal inflammation when the body was subject to H. pylori invasion. Thus, CD8⁺ T cells might mediate gastric mucosal inflammation when H. pylori infects the body. CTL-mediated gastric mucosal immune response was predominant when H. pylori invaded the organism [23]. Helicobacter urease suppresses cytotoxic CD8⁺ T-cell responses through activating Myh9-dependent induction of PD-L1 [24].

3. H. pylori infection associated with B cells

The primary function of B cells is to produce antibodies to mediate the humoral immune response. When H. pylori invades the gastric mucosa, B cells limit the invasion and metastasis of H. pylori by secreting antibodies to confine H. pylori to a specific lesion. The proliferative effect of CD8⁺ T cells in the blood of patients infected with H. pylori by flow cytometry found that B cells could stimulate the increase of CD8⁺ T cells after the binding of H. pylori to the gastric mucosa. The results suggested that this may be one of the mechanisms by which B cells are involved in the fight against H. pylori infection and mediate the inflammatory response of gastric mucosal tissues. Regulatory B cells, similar to Treg, can mediate the inflammatory immune response to H. pylori infection of the gastric mucosa [25]. A research team produced a C57BL/6 mouse model infected with H. pylori Sydney strain (HPSS1) by gavage and found that Foxp3⁺ Treg and IL-10-secreting regulatory B cells (IL-10, HPSS1, HPSS1, HPSS1, HPSS1, HPSS1, HPSS1, HPSS1, HPSS1, HPSS1, HPSS1, and IL-10-secreting regulatory B cells (IL-10) were the most critical factors in the inflammatory response. The higher number of Foxp3⁺ Treg and IL-10⁺ B cells (the earlier increase of IL-10⁺ B cells compared with Foxp3⁺ Treg) suggested that IL-10⁺ B cells could allow H. pylori to escape from the attack at the early stage of infection and persistently colonize the surface of the gastric mucosa, which could then release inflammatory factors to cause gastric mucosal tissue damage. In addition, IL-10⁺ B cells and Foxp3⁺ Treg content in the small intestine and colon mucosa were significantly increased, suggesting that H. pylori infection may cause damage to the mucosa of the small intestine and colon [26]. H. pylori deregulates T- and B-cell signaling to trigger immune evasion [27].

4. H. pylori infection associated with NK cells

NK cells are a class of nonspecific immune lymphocytes different from T and B cells and directly kill target cells. NK cells regulate the host’s immune function by releasing inflammatory factors, such as IFN-γ and TNF-α. Some cytokines, such as IL-12 and TNF-α, can regulate NK cell function and induce NK cells to produce IFN-γ. NK cells are the primary effector cells exerting an intrinsic immune response in the gastric mucosa against H. pylori infection. Recently, it was found that NK cells could participate in the inflammatory response of H. pylori-infected gastric mucosal tissues by releasing IL-12 and IFN-γ, which can be mediated by natural killer group 2, an activating receptor whose ligand (NKG2DL) expression is induced in conditions of cell stress and carcinogenesis transformation [28]. NK cells can secrete IFN-γ, and chronic inflammation in the stomach of H. pylori-infected people is mainly characterized by increased IFN-γ secretion, suggesting that NK cells mediate the inflammatory immune response at the same time as clearing H. pylori infection. IL-12 can stimulate the production of IFN-γ by NK cells through H. pylori or toll-like receptor (TLR)2 ligands [29]. The expression of the costimulatory molecule CD86 and the proliferation of CD56⁺ NK cells were associated with high-grade MALT at the early stage of H. pylori infection, suggesting that CD56⁺ NK cells may be involved in the pathogenesis of high-grade gastric MALT lymphoma.

5. H. pylori infection associated with dendritic cells

In DCs infected with H. pylori, synergistic interactions regulate IL-1β secretion between cagPAI and the TLR2, NOD2, and NLRP3 triad, modulating the inflammatory immune response [30]. DCs are predominantly known for their function as a potent inductive agent of adaptive immunity. DCs exposed to H. pylori in vitro or in vivo cannot induce T-cell effector functions. Instead, they efficiently induced the expression of the forkhead transcription factor FoxP3, the master regulator of Treg. DC depletion resulted in better infection control and aggravated T-cell-driven immunopathology [31]. Mucosal CD11c dendritic cells are located near the surface of normal gastric epithelium and increase after H. pylori infection. The depletion of CD25 Tregs results in an early reduction of H. pylori density, correlated with enhanced peripheral H. pylori-specific Th17, but not Th1 response [32]. Th17, not Th1, response during H. pylori infection is related to a lower level of H. pylori colonization in HP-DC-transferred mice. All in all, the mechanism of immune escape of H. pylori through the induction of Tregs impedes Th17 immunity [32].

6. H. pylori infection associated with macrophages

Macrophages are critical immune cells in the defense of gastric mucosal tissues against H. pylori infection, and they mainly work together with reactive oxygen species and reactive nitrogen to clear H. pylori through secreted inflammatory cytokines TNF-α, IL-1, IL-6, and IL-17 [33]. When H. pylori infects gastric mucosal tissues, macrophages migrate large numbers from the peripheral blood to the infected gastric mucosal tissues for immunomodulation. At the same time, macrophages secrete inflammatory factors that damage the gastric mucosal tissues. BAFF is a pivotal cytokine that impacts the activity of both innate and adaptive immune cells. The expression of IL-17 and BAFF was higher in chronic gastritis patients infected with H. pylori, and BAFF cytokines released by macrophages not only altered immune cell activity but also could promote Th17 proliferation, suggesting that macrophages could elicit gastric mucosal inflammatory immune responses through the BAFF/Th17 signaling pathway [34]. The correlation between the immune cells with H. pylori infection that are referred to the above is summarized in the Figure 1.

Figure 1.

The change of immune cells in the pathogenesis of gastric mucosa after H. pylori infections.

7. H. pylori infection associated with immune molecules

We will elaborate on the membrane molecular, cytokine, and signal pathway related to H. pylori infection which are summarized in the Table 1. Toll-like receptor (TLR)-mediated sensing of microbial molecular patterns and corresponding signaling is one of the primary innate immune mechanisms against intruding pathogens. TLRs also play a significant role in innate and adaptive immune responses against H. pylori. The concentration of TLR2 and TLR4 is higher in H. pylori-positive participants compared to the control group [35]. TLR2, TLR4, and TLR10 can shape the cytokine and chemokine release of H. pylori-infected human DCs [36]. H. pylori infection induces IL-10 secretion in DCs, which activates STAT3, thereby modulating DC maturation and reducing IL-1β secretion [37]. H. pylori cytotoxin-associated gene A (Cag A) impairs human dendritic cell maturation and function through IL-10-mediated activation of STAT3 [38]. STAT3 links IL-22 signaling in intestinal epithelial cells to modulate mucosal wound healing [39].

	H. pylori infection	Gastric cancer
Cell types	CD4^+T cell, CD8^+T cell, NK cell, B cell, Macrophage, DC	CD4^+T cell, CD8^+T cell, B cell, Tumor-Associated Macrophages
Molecules	TLR2, TLR, TLR10, B7H3, SOCS3, CCR2, CXCL2, MMP10, ITGB1	PD-L1, FGFR4, MMPs, CTLA-4, CD44
	IL23, IL33, BAFF, T cell derived cytokines	IL6, IL-10, IL-17A
	STAT3, NF-κB, NLRP3, MyD88	STAT1, STAT3, NF-κB

Table 1.

The dynamic change of immune and non-immune cells during H. pylori infection and gastric cancer.

A search team found a new regulatory mechanism employed by H. pylori to influence the type of the T-cell response. GEC cocultures and anti-B7-H3 blocking Ab confirmed that the induction of Th2 is mediated by B7-H3 and associated exclusively with an H. pylori gastritis strain, not cancer or ulcer strains [40]. High levels of SOCS3 in DCs dampen PD-L1 expression in DCs, which drives T-cell proliferation [41]. CagA interacts with ITGB1, causing gastric mucosa cells to produce IL-8. ITGB1 deficiency can inhibit phosphorylation and activation of p38 and ERK1/2 by CagA [42].

Helicobacter pylori-induced IL-33 modulates mast cell responses and favors bacterial growth [43]. IL-33 can limit immunopathology by promoting T helper 2 immune response. H. pylori activates NF-κB signaling via the pathogen recognition molecule nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and its receptor to promote and process IL-33 [44]. Mice lacking expression of the CCL2 receptor CCR2 are incapable of responding to H. pylori infection [45]. One of the consequences of NF-κB activation in gastric epithelial cells is the production of chemokine CCL2, which serves as a central chemokine attracting myeloid cells to infectious tissues [46]. After H. pylori infection, IL-23-induced Th22 cells are rapidly increased in the gastric mucosa, and Th22 can secrete IL-22, which increases CXCL2 production by the gastric mucosa. CXCL2 was combined with its corresponding receptors, leading to migrating myeloid-derived suppressor cells (MDSCs) toward the gastric epithelium. In response to IL-22 induction, MDSCs produce the proinflammatory factors, calgranulin A (S100A8) and S100A9, and directly inhibit the development of Th1 cells, leading to gastritis progression [10]. Moreover, through activation of the signaling pathway of the ERK, H. pylori synergistically promotes the production of matrix metalloproteinases (MMPs), especially MMP-10, in gastric epithelial cells. According to former research, MMP-10 can stimulate bacterial colonization by inhibiting the production of antimicrobial peptides in gastric epithelial cells. In addition, MMP-10 also induces gastric epithelial cells to secrete the chemokine CXCL16, which recruits CD8⁺ T cells to the gastric mucosa and exacerbates the inflammatory response [47]. Also, NLRP3−/−mice cannot activate Treg responses to H. pylori and control the infection more effectively than wild-type mice. The results demonstrate NLRP3 is crucial to Treg development and suppression of Th1 responses. Besides, they emphasized the inflammasome-independent function of NLRP3 in DC evolution and immune regulation [45]. H. pylori activates different TLR/MyD88 signaling pathways, initiating immune responses that lead to different responses and resultant cascades. This differential pathway activation may depend on the type of H. pylori ligand, host TLR source, and species, recruited MyD88 and its downstream molecules, or other host-related factors, even related to different models of TLR ectopic expression [48].

8. Dynamic changes in gastric cancer

Chronic H. pylori infection causes long-lasting inflammation in the stomach, which can lead to several possible conditions, including atrophic gastritis (thinning of the stomach lining caused by long-term inflammation) and certain types of stomach (gastric) cancer, particularly gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which is a rare type of non-Hodgkin lymphoma. After elaborating on the relative immune cells and molecules of H. pylori infection, we will demonstrate how these immune cells and molecules influence gastric cancer development.

Compared with the normal tissue, Treg cells in gastric cancer increased remarkably [49]. However, relevant transcriptional regulators still need more research to identify [50].

Kynureninase (KYNU), a biomarker of tumor-associated macrophages, is related to the immunosuppressive microenvironment in gastric cancer [51], suggesting the involvement of macrophages in GC. Moreover, converting M2-type TAMs back into M1-type (reprogramming of TAMs) is effective in antitumor therapy in tumor microenvironment (TME) [52]. Cyclase-associated protein 2 (CAP2) promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages. M2 macrophage-derived TGFβ1 can influence the activation of M2 macrophage by a TGF β1/JUN/CAP2 positive-feedback loop [53].

H. pylori protein, CagY, can drive both B-cell proliferation and T-cell activation in gastric MALT lymphomas [5]. As to the cytokine levels of gastric cancer, a meta-analysis explored the association between proinflammatory cytokines and GC, of which 61 studies investigating cytokine serum levels were included [54]. They found that patients with GC were found to have significantly elevated levels of IL-6, IL-7, IL-10, IL-12, and TNF-α. IL-6 is one of the most crucial inflammatory cytokines in the action of H. pylori-accompanied gastric cancer. From the mechanism perspective, IL-6 activates gastric inflammation and stimulates a proliferative response of the gastric cell. However, long-lasted gastric injury leads to the development of chronic gastritis and inflammation-induced gastric cancer [55]. During atrophic gastritis to dysplasia to gastric cancer, CD44 is significantly increased in individuals, which is related to the IFN-γ production [56]. STAT3 is a proinflammatory oncogenic transcription factor that mediates tumor initiation and progression in several cancer types, including gastric cancer [57]. In H. pylori-induced gastritis and gastric carcinogenesis, H. pylori-induced STAT3 activation is mediated, at least in part, through ROS-induced upregulation of IL-6 expression [58]. Macrophages after H. pylori infection can release cytokine BAFF. BAFF can drive Th17 responses both indirectly by creating a pro-Th17 cytokine milieu through the involvement of innate immune cells and directly via the differentiation of T cells toward the specific profile [34]. A recent study shows that IL-17A promotes gastric carcinogenesis, in part, by regulating the IL-17RC/NF-κB/NOX1 pathway [59]. H. pylori-induced activation of STAT1 and PD-L1 expression may prevent immune surveillance in the gastric mucosa, allowing premalignant lesions to progress to gastric cancer [60]. Various pathogen-associated molecular patterns (PAMPs) derived from bacteria can bind to different TLRS. After H. pylori infection, pathogen-associated molecular patterns (PAMPs) derived from bacteria can attach to different TLRs. When TLR recruits IRAK, TRAF88, and TAK6 to activate the IKK complex and phosphorylate IκB, TLR mediates MYD1-dependent pathways that induce downstream NF-κB programs to promote inflammation and immune responses [48].

Fibroblast growth factor receptors (FGFRs) are a gene family of transmembrane tyrosine kinase receptors that activate critical downstream signaling pathways [61]. FGFR4 overexpression is relevant to the biology of gastric cancer. Also, FGFR4 protects gastric cancer cells from apoptosis during H. pylori infection [62]. Moreover, the migration and invasion of GC are mainly associated with MMP2, MMP9 [63], IL-1β [64], and CXCL8 [65]. The Table 1 summarizes the molecules involved in the H. pylori infection and gastric cancer process.

9. Conclusion

Recently, there has been prominent progress in accessing the pathogenesis, diagnosis, and treatment of H. pylori infection. This has led to a substantial decline in the incidence of peptic ulcers and a distinct potential for preventing gastric cancer. TME also featured a variety of inflammatory cytokines and chemokines, including CXCL2, IL-1, IL-6, GM-CSF, and IFN-γ. Intricate interactions between immune cells with cytokines and cancer cells promote cancer progression [48]. In the gastric mucosa, H. pylori promotes the differentiation of tolerogenic DCs, M2 macrophages, and Treg cells; inhibits the Th1/Th17 response; and/or sequesters CD8⁺ T cells [13]. H. pylori and cytokine gene variants as predictors of premalignant gastric lesions have been emphasized. An association between anti-H. pylori IgG titers and the TLR1/6/10 locus with top SNP rs12233670 was demonstrated in the discovery phase using the fixed-effect model [66]. Throughout some meta-analyses, IL-6 is one of the most critical inflammatory cytokines in the action of H. pylori-associated gastric cancer. Maybe it is too early to either confirm or rule out a role for TLR1 loci as genetic risk factors for H. pylori infection. Inherited variation of the TLR1/6/10 locus confers immunologic cellular consequences, but high heterogeneity, cohort differences, and antibody decay likely prevent the replication of previous associations with anti-H. pylori IgG. In gastric cancer, H. pylori infection increases the expression of tyrosine kinases, such as FYN, AKT3, MAPK, YES, SRC, PDK1, and mTOR. H. pylori activates and secretes proinflammatory cytokines via activated signaling pathways, causing gastric cancer development. The inflammatory immune response induced by H. pylori cannot completely clear H. pylori and, worse still, induce localized inflammatory damage to the gastric mucosa. Relevant dynamic changes of host immune response during the H. pylori-induced gastric carcinogenesis deserve more investigation.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant Number 82270592).

Authorship

W.F. conceived the proposal. M.Z. prepared the manuscript. W.F., J.Z., and S.D. revised the manuscript.

Disclosures

The authors declare no conflicts of interest.

Abbreviations

BAFF, B-cell	activating factor
CagA	cytotoxin-associated gene A
cagPAI	cag pathogenicity island
CAP2	cyclase-associated protein 2
CCR6	chemokine receptor 6
CTL	cytotoxic T lymphocyte
DC	dendritic cell
ERK	extracellular signal-regulated kinases
FGFRs	fibroblast growth factor receptors
GC	gastric cancer
γGT	γ-glutamyl transpeptidase
hMDCs	human monocyte-derived dendritic cells
HPSS1	H. pylori sydney strain 1
H. pylori	Helicobacter pylori
IFN	interferon
IL	interleukins
IRAK	interleukin-1 receptor (IL-1R)-associated kinase
KYNU	kynureninase
MALT	mucosa-associated lymphoid tissue
MDSCs	myeloid-derived suppressor cells
MMPs	matrix metalloproteinases
MyD88	myeloid differentiation primary response 88
NLRP3	NLR family pyrin domain containing 3
NOD1	nucleotide-binding oligomerization domain-containing protein 1
NK	natural killer
PAMPs	pathogen-associated molecular patterns
PBMCs	peripheral blood mononuclear cells
TAMs	tumor-associated macrophages
TGF-β	transforming growth factor β
Th	T helper
TLR	toll-like receptor
TME	tumor microenvironment
Tregs	regulatory T cells
T + RM phenotype	tissue-resident memory (TRM) phenotype;
UreB	urease subunit B
VacA	vacuolar cytotoxin A.