Gut OncoMicrobiome Signatures (GOMS) As Next-Generation Biomarkers for Cancer Immunotherapy

Oncogenesis is associated with intestinal dysbiosis, and stool shotgun metagenomic sequencing in individuals with this condition might constitute a non-invasive approach for the early diagnosis of several cancer types. The prognostic relevance of antibiotic intake and gut microbiota composition urged investigators to develop tools for the detection of intestinal dysbiosis to enable patient stratification and microbiota-centred clinical interventions. Moreover, since the advent of immune-checkpoint inhibitors (ICIs) in oncology, the identification of biomarkers for predicting their efficacy before starting treatment has been an unmet medical need. Many previous studies addressing this question, including a meta-analysis described herein, have led to the description of Gut OncoMicrobiome Signatures (GOMS). In this Review, we discuss how patients with cancer across various subtypes share several GOMS with individuals with seemingly unrelated chronic inflammatory disorders who, in turn, tend to have GOMS different from those of healthy individuals. We discuss findings from the aforementioned meta-analysis of GOMS patterns associated with clinical benefit from or resistance to ICIs across different cancer types (in 808 patients), with a focus on metabolic and immunological surrogate markers of intestinal dysbiosis, and propose practical guidelines to incorporate GOMS in decision-making for prospective clinical trials in immuno-oncology

Nox2-deficient Tregs improve heart transplant outcomes via their increased graft recruitment and enhanced potency.

Nox2 is a ROS-generating enzyme, deficiency of which increases suppression by Tregs in vitro and in an in vivo model of cardiac remodelling. Since Tregs have emerged as a candidate therapy in autoimmunity and transplantation, we hypothesised that Nox2 deficiency in Tregs in recipient mice may improve outcomes in a heart transplant model. A novel B6129 mouse model with Treg-targeted Nox2 deletion (Nox2fl/flFoxP3Cre+) was generated and transplanted with hearts from CB6F1 donors. As compared to littermate controls, Nox2fl/flFoxP3Cre+ mice had lower plasma levels of alloantibodies and troponin-I, reduced levels of IFN-γ in heart allograft homogenates and diminished cardiomyocyte necrosis and allograft fibrosis. Single cell analyses of allografts revealed higher absolute numbers of Tregs and lower CD8+ T cell infiltration in Nox2-deficient recipients compared to Nox2-replete mice. Mechanistically, in addition to a greater suppression of CD8+CD25- T effector cell proliferation and IFN-γ production, Nox2-deficient Tregs expressed higher levels of CCR4 and CCR8, driving cell migration to allografts; this was associated with increased expression of miR214-3p. These data indicate that Nox2 deletion in Tregs enhances their suppressive ability and migration to heart allografts. Therefore, Nox2 inhibition in Tregs may be a useful approach to improve their therapeutic efficacy

Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial

Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune tonus, earned its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years (p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii, and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation

Rôle des antibiotiques dans la résistance à l'immunothérapie anticancéreuse par anticorps monoclonal anti-PD-1

La méta-analyse d’études rétro- et prospectives montre que la prise d’antibiotiques (ATB) compromet la réponse aux immunothérapies à base d’inhibiteurs de point de contrôle immun (ICBs). Nous avons émis l’hypothèse que les cellules immunitaires d’origine intestinale, caractérisées par l’expression de l’intégrine α4β7 sont impliquées dans ce processus à cause du lien étroit entre la composition du microbiote intestinal et la réponse aux ICBs. L’expression d’α4β7 par les leucocytes intestinaux permet leur interaction avec une molécule d’adhésion spécifique de l’endothélium intestinal, MAdCAM-1. Nous avons découvert que la dysbiose induite par la prise d’ATB promeut la recirculation de cellules lymphocytaires T α4β7+ CD4+ d’origine iléale jusqu’au micro-environnement tumoral (MET). En induisant une diminution de l’expression intestinale de MAdCAM-1, la recolonisation après la prise d’ATB conduit à l’accumulation de cellules α4β7+RORγt+FoxP3+ Tr17 régulatrices d’origine iléale dans le MET. L’altération de l’axe α4β7/MAdCAM-1, soit chez des souris déficientes pour les gènes codant la protéine MAdCAM-1 ou l’intégrine beta7 ou à l’aide d’anticorps bloquants MAdCAM-1 ou α4β7 chez la souris compromet l’efficacité de l’anti-PD-1. La normalisation de l’expression de MAdCAM-1 dans l’intestin par la modification de la composition du microbiote intestinal à l’aide de probiotiques ou par la transplantation de microbiote fécal permet de restaurer la réponse à l’anti-PD-1 lors d’une dysbiose induite par ATB chez la souris. En conclusion, l’immunosurveillance du cancer est modulée par le dialogue entre l’intestin et la tumeur de façon dépendante de l’axe α4β7/MAdCAM-1 et de la composition du microbiote intestinal. Ces travaux ouvrent la voie à de nombreuses interventions thérapeutiques visant à normaliser l’expression intestinale de MAdCAM-1, en modulant notamment le microbiote intestinal, chez des patients éligibles aux ICBs pour améliorer leur devenir clinique.Meta-analysis on all available retro- and prospective studies showed that antibiotics (ATB) compromise the outcome of immune checkpoint blockers (ICBs). We assumed gut immune cells, characterized by α4β7 integrin expression, were implicated in the process because of the intricate relation between gut microbiota composition and response to ICBs. The leukocyte expression of α4β7 integrin enables binding to Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) mostly expressed on endothelial cells in the intestine. We have discovered that ATB-induced intestinal dysbiosis promotes the egress of enterotropic ileal α4β7+ CD4+ T cells from the intestine to extraintestinal tumor microenvironment (TME). By inducing the downregulation of ileal MAdCAM-1 gene and protein expression in the intestine, gut bacterial recolonization after the ATB course provoked the accumulation of ileal α4β7+RORγt+FoxP3+ regulatory Tr17 cells into the TME. In mouse models, resistance to ICBs was induced by using MAdCAM-1 or ITGB7 genetic deficiencies or antibody neutralization of the MAdCAM-1/α4β7 axis. Maneuvers aimed at normalizing MAdCAM-1 expression in the intestine trough the modification of the gut microbiota composition with probiotics or fecal microbiota transplantation prevented the ATB-induced immunosuppressive effects on PD-1 blockade. Hence, cancer immunosurveillance is governed by a gut-tumor dialogue involving the MAdCAM-1/α4β7 axis modulated by gut microbiota composition. This work opens the door to relevant clinical interventions relying on the intestinal α4β7/MAdCAM-1 axis and gut microbiota monitoring and thus to maneuvers expected to normalize MAdCAM-1 gut expression in patients eligible to ICBs with the aim of optimize their outcome

Microbiota-associated immunotherapy resistance caused by deficient PD-L2 - RGMb signaling

ABSTRACTIn a recent paper in Nature, Park et al. propose a mechanism through which intestinal dysbiosis compromises the efficacy of immunotherapy targeting the PD-L1/PD−1 interaction. Dysbiosis may upregulate a pair of checkpoint molecules, i.e. PD-L2 interacting with RGMb. Antibodies targeting PD-L2/RGMb can restore responses to PD−1 blockade in the context of dysbiosis

Bile acids regulate MAdCAM-1 expression to link the gut microbiota to cancer immunosurveillance

ABSTRACTIn a recent paper in Science, Fidelle et al. unravel a gut immune checkpoint that is subverted by antibiotic treatment. Post-antibiotic dysbiosis of the ileum causes an increase in bile acids that downregulate MAdCAM−1, thereby triggering the exodus of immunosuppressive T cells from gut-associated lymphoid tissues toward tumors

Epidemiological Study to Assess the Prevalence of Lung Cancer in patients with smoking-associated atherosclerotic cardiovascular diseases: PREVALUNG study protocol

International audienceEligibility criteria definition for a lung cancer screening (LCS) is an unmet need. We hypothesised that patients with a history of atheromatous cardiovascular disease (ACVD) associated with tobacco consumption are at risk of lung cancer (LC). The main objective is to assess LC prevalence among patients with ACVD and history of tobacco consumption by using low-dose chest CT scan. Secondary objectives include the evaluation LCS in this population and the constitution of a biological biobank to stratify risk of LC

Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

International audienceAccumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients