The Efficacy of Cancer Immunotherapies Is Compromised by Helicobacter pylori Infection.

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.

GM-CSF is key in the efficacy of vaccine-induced reduction of Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori (H. pylori) colonizes the human gastric mucosa with a high worldwide prevalence. Currently, H. pylori is eradicated by the use of antibiotics. However, elevated antibiotic resistance suggests new therapeutic strategies need to be envisioned: one approach being prophylactic vaccination. Pre-clinical and clinical data show that a urease-based vaccine is efficient in decreasing H. pylori infection through the mobilization of T helper (Th) cells, especially Th17 cells. Th17 cells produce interleukins such as IL-22 and IL-17, among others, and are key players in vaccine efficacy. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing Th17 cells have been identified. AIM: This study explores the possibility that GM-CSF plays a role in the reduction of H. pylori infection following vaccination. RESULTS: We demonstrate that GM-CSF+ IL-17+ Th17 cells accumulate in the stomach mucosa of H. pylori infected mice during the vaccine-induced reduction of H. pylori infection. Secondly, we provide evidence that vaccinated GM-CSF deficient mice only modestly reduce H. pylori infection. Conversely, we observe that an increase in GM-CSF availability reduces H. pylori burden in chronically infected mice. Thirdly, we show that GM-CSF, by acting on gastric epithelial cells, promotes the production of ßdefensin3, which exhibits H. pylori bactericidal activities. CONCLUSION: Taken together, we demonstrate a key role of GM-CSF, most probably originating from Th17 cells, in the vaccine-induced reduction of H. pylori infection.

Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies.

OBJECTIVE: In this study, we determined whether Helicobacter pylori (H. pylori) infection dampens the efficacy of cancer immunotherapies. DESIGN: Using mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective in reducing tumour volumes of H. pylori-infected mice. In humans, we evaluated the correlation between H. pylori seropositivity and the efficacy of the programmed cell death protein 1 (PD-1) blockade therapy in patients with non-small-cell lung cancer (NSCLC). RESULTS: In mice engrafted with MC38 colon adenocarcinoma or B16-OVA melanoma cells, the tumour volumes of non-infected mice undergoing anticytotoxic T-lymphocyte-associated protein 4 and/or programmed death ligand 1 or anti-cancer vaccine treatments were significantly smaller than those of infected mice. We observed a decreased number and activation status of tumour-specific CD8+ T cells in the tumours of infected mice treated with cancer immunotherapies independent of the gut microbiome composition. Additionally, by performing an in vitro co-culture assay, we observed that dendritic cells of infected mice promote lower tumour-specific CD8+ T cell proliferation. We performed retrospective human clinical studies in two independent cohorts. In the Dijon cohort, H. pylori seropositivity was found to be associated with a decreased NSCLC patient survival on anti-PD-1 therapy. The survival median for H. pylori seropositive patients was 6.7 months compared with 15.4 months for seronegative patients (p=0.001). Additionally, in the Montreal cohort, H. pylori seropositivity was found to be associated with an apparent decrease of NSCLC patient progression-free survival on anti-PD-1 therapy. CONCLUSION: Our study unveils for the first time that the stomach microbiota affects the response to cancer immunotherapies and that H. pylori serology would be a powerful tool to personalize cancer immunotherapy treatment.

Gastric eosinophils are detrimental for Helicobacter pylori vaccine efficacy.

Helicobacter pylori (Hp) colonizes the human gastric mucosa with a high worldwide prevalence. Currently, Hp can be eradicated by the use of antibiotics. Due to the increase of antibiotic resistance, new therapeutic strategies need to be devised: one such approach being prophylactic vaccination. Pre-clinical and clinical data showed that a urease-based vaccine is efficient in decreasing Hp infection through the mobilization of T helper (Th)-dependent immune effectors, including eosinophils. Preliminary data have shown that upon vaccination and subsequent Hp infection, eosinophils accumulate in the gastric mucosa, suggesting a possible implication of this granulocyte subset in the vaccine-induced reduction of Hp infection. In our study, we confirm that activated eosinophils, expressing CD63, CD40, MHCII and PD-L1 at their cell surface, infiltrate the gastric mucosa during vaccine-induced reduction of Hp infection. Strikingly, we provide evidence that bone marrow derived eosinophils efficiently kill Hp in vitro, suggesting that eosinophils may participate to the vaccine-induced reduction of Hp infection. However, conversely to our expectations, the absence of eosinophils does not decrease the efficacy of this Hp vaccine in vivo. Indeed, vaccinated mice that have been genetically ablated of the eosinophil lineage or that have received anti-Sialic acid-binding immunoglobulin-like lectin F eosinophil-depleting antibodies, display a lower Hp colonization when compared to their eosinophil sufficient counterparts. Although the vaccine induces similar urease-specific humoral and Th responses in both eosinophil sufficient and deficient mice, a decreased production of anti-inflammatory cytokines, such as IL-10, TGFß, and calgranulin B, was specifically observed in eosinophil depleted mice. Taken together, our results suggest that gastric eosinophils maintain an anti-inflammatory environment, thus sustaining chronic Hp infection. Because eosinophils are one of the main immune effectors mobilized by Th2 responses, our study strongly suggests that the formulation of an Hp vaccine needs to include an adjuvant that preferentially primes Hp-specific Th1/Th17 responses.