The immune microenvironment in gastric adenocarcinoma

Abstract

Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.

Figure 1 ∣. Timeline of complications from Helicobacter pylori infection.

A schematic of the timeline from H. pylori infection to the development of gastric ulcers versus gastric atrophy, intestinal metaplasia, dysplasia and gastric cancer. Key genomic changes were identified by profiling of human gastric intestinal metaplasia and cancer^,. Vertical arrows indicate direction of the change; for example, FBXW7 mutations identified in intestinal metaplasia and more numerous in the WD40 domain are represented by larger arrow. Bidirectional arrow indicates increase or decrease. Infection of the gastric mucosa initiates acute inflammatory responses most of which result in an increase in NFκB. Injured parietal cells release Shh within 2 days of the infection and Shh can be detected in the circulation, which subsequently recruits myeloid cells to the stomach. Why some individuals do not develop atrophy and instead develop duodenal ulcers owing to the hyperacidity is unknown, but RNA and DNA profiling suggests that hypermethylation, loss of parietal cells and a LOF in the ubiquitin ligase FBXW7 are early steps that lead to the pathway from intestinal metaplasia to GAC.

Figure 2 ∣. PMC-MDSC induction during spasmolytic polypeptide-expressing metaplasia (SPEM) development.

Acutely, Slfn4⁺ myeloid-derived suppressor cells (MDSCs) regulated by Shh signalling track to the stomach, but do not develop their T-cell suppressor function until levels of tissue IFNα produced by plasmacytoid dendritic cells (pDCs) increase. SPEM development coincides with maximal expression of Slfn4 and the Slfn4⁺ MDSCs acquire T-cell suppressor function ^,. Slfn4⁺-MDSCs express NFκB and secrete regulatory microRNAs such as MIR130b. DAMPs, damage-activated molecular patterns.

Figure 3 ∣. Differentiation and cell signatures of common immune cells recruited to the stomach in response to H. pylori infection.

Within the bone marrow, hematopoietic stem cells (HSCs) differentiate into common myeloid progenitor cells (CMPs) that then give rise to granulocyte-macrophage progenitors (GMPs). GMPs differentiate into myeloblasts, promyeloblasts, myelocytes and granulocytes in response to granulocyte colony-stimulating factor (G-CSF). By contrast, macrophage colony-stimulating factor (M-CSF) induce GMP differentiation towards monocytes, macrophages or dendritic cells via monocyte/macrophage and dendritic cell progenitors (MDPs). In response to specific environmental cues, hemangiocytes, TIE2-expressing monocytes (TEMs), monocytes, dendritic cells, MDSCs, neutrophils, eosinophils and immature mast cells all originate from the same HSC and circulate within the blood. Once recruited to the stomach in response to H. pylori infection or tissue injury, these immune cells express specific cell signatures that orchestrate neovascularization, create an immune suppressive environment and lead to development of metaplasia ^,,,,,-. APC, antigen- presenting cell; IM, intestinal metaplasia; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; M- MDSC, monocytic myeloid- derived suppressor cell; PMN, polymorphonuclear; SPEM, spasmolytic polypeptide- expressing metaplasia.