A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4ß7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4ß7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4ß7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.

IL-22BP production is heterogeneously distributed in Crohn's disease.

Crohn's disease (CD), a form of inflammatory bowel disease (IBD), is characterized by impaired epithelial barrier functions and dysregulated mucosal immune responses. IL-22 binding protein (IL-22BP) is a soluble inhibitor regulating IL-22 bioactivity, a cytokine proposed to play protective roles during CD. We and others have shown that IL-22BP is produced in IBD inflamed tissues, hence suggesting a role in CD. In this work, we extended the characterization of IL-22BP production and distribution in CD tissues by applying enzyme-linked immunosorbent assays to supernatants obtained from the culture of endoscopic biopsies of patients, and reverse transcription-quantitative polymerase chain reaction on sorted immune cell subsets. We reveal that IL-22BP levels are higher in inflamed ileums than colons. We observe that in a cell-intrinsic fashion, populations of mononuclear phagocytes and eosinophils express IL-22BP at the highest levels in comparison to other sources of T cells. We suggest the enrichment of intestinal eosinophils could explain higher IL-22BP levels in the ileum. In inflamed colon, we reveal the presence of increased IL-22/IL22BP ratios compared to controls, and a strong correlation between IL-22BP and CCL24. We identify monocyte-derived dendritic cells (moDC) as a cellular subtype co-expressing both cytokines and validate our finding using in vitro culture systems. We also show that retinoic acid induces the secretion of both IL-22BP and CCL24 by moDC. Finally, we report on higher IL-22BP levels in active smokers. In conclusion, our work provides new information relevant to therapeutic strategies modulating IL-22 bioactivity in CD, especially in the context of disease location.

Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy.

While immune checkpoint (IC) therapies, particularly those targeting the PD-1/PD-L1 axis, have revolutionized the treatment of melanoma and several other cancers, their effect remains very limited in colorectal cancer (CRC). To define a comprehensive landscape of ICs in the human CRC tumor microenvironment (TME), we evaluated, using multiparametric flow cytometry, their ex vivo expression via tumor-infiltrating lymphocytes (TILs) (n = 40 CRCs) as well as that of their respective ligands on tumor and myeloid cells (n = 29). Supervised flow cytometry analyses showed that (i) most CD3+ TILs expressed PD-1 and TIGIT and, to a lesser extent, Tim-3, Lag3 and NKG2A, and (ii) EpCAM+ tumor cells and CD11b+ myeloid cells differed in their IC ligand expression profile, with a strikingly high expression of CD155 by tumor cells. An in situ analysis of IC and their ligands using immunohistochemistry on paraffin sections of CRC confirmed the overexpression of TIGIT and its ligand, CD155, in the TME. Most interestingly, an unsupervised clustering analysis of IC co-expression on CD4+ and CD8+ TILs identified two tumor subgroups, named IChigh and IClow. Altogether, our findings highlight the TIGIT/CD155 axis as a potential target that could be used in combination IC therapy in CRC.

Targeting NKG2A to boost anti-tumor CD8 T-cell responses in human colorectal cancer.

Recently, the inhibitory CD94/NKG2A receptor has joined the group of immune checkpoints (ICs) and its expression has been documented in NK cells and CD8+ T lymphocytes in several cancers and some infectious diseases. In colorectal cancer (CRC), we previously reported that NKG2A+ tumor-infiltrating lymphocytes (TILs) are predominantly CD8+ αß T cells and that CD94 overexpression and/or its ligand HLA-E were associated with a poor prognosis. This study aimed to thoroughly characterize the NKG2A+ CD8+ TIL subpopulation and document the impact of NKG2A on anti-tumor responses in CRC. Our findings highlight new features of this subpopulation: (i) enrichment in colorectal tumors compared to paired normal colonic mucosa, (ii) their character as tissue-resident T cells and their majority terminal exhaustion status, (iii) co-expression of other ICs delineating two subgroups differing mainly in the level of NKG2A expression and the presence of PD-1, (iv) high functional avidity despite reduced proliferative capacity and finally (v) inhibition of anti-tumor reactivity that is overcome by blocking NKG2A. From a clinical point of view, these results open a promising alternative for immunotherapies based on NKG2A blockade in CRC, which could be performed alone or in combination with other IC inhibitors, adoptive cell transfer or therapeutic vaccination.

Early remodeling of the colonic mucosa after allogeneic hematopoietic stem cells transplantation: An open-label controlled pilot study on 19 patients.

BACKGROUND: Graft-versus-host disease (GVHD), particularly acute digestive GVHD (aDGVHD), is a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is necessary to identify predictive factors of GVHD to adapt prophylactic treatment. OBJECTIVE: In this context, our pilot study aimed (i) to determine whether an early remodeling of the colonic mucosa occurred after allo-HSCT and (ii) to identify potential predictive mucosal markers of aDGVHD after allo-HSCT. METHODS: Between day 21 and day 28 after the allo-HSCT, 19 allo-HSCT patients were included and had a rectosigmoidoscopy with probe-based confocal laser endomicroscopy (pCLE) recording and biopsies. Sixteen patients were included in the control group. Morphological (pCLE), functional (intestinal permeability), and inflammatory parameters (cytokine multiplex immunoassay) were assessed. RESULTS: Among allo-HSCT patients, 11 patients developed GVHD, and 6 of them developed aDGVHD. Morphological and functional changes of the colonic mucosa occurred after allo-HSCT. Indeed, the perimeter of colonic crypts was significantly increased in allo-HSCT patients compared to controls as well as crypt lumen fluorescein leakage (53% vs. 9%), whereas crypts sphericity, roundness, Feret diameter, and mean vessel area were significantly decreased in allo-HSCT patients compared to the control group. In addition, interleukin-6 (IL-6), IL-33, and IL-15 levels in the supernatants of 24 h explant cultures of colonic biopsies were significantly increased in allo-HSCT patients compared to controls. Finally, there was no difference in pCLE parameters, intestinal permeability, and inflammatory cytokines between patients who developed aDGVHD and those who did not. CONCLUSION: This pilot study identified early colonic mucosa remodeling after allo-HSCT conditioning therapy, that is morphological and functional mucosal alterations as well as mucosal inflammation. As to whether these changes are first steps in GVHD initiation and could be considered as predictive biomarkers of aDGVHD need to be determined in a larger cohort of patients.

PGI2 Inhibits Intestinal Epithelial Permeability and Apoptosis to Alleviate Colitis.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) that encompass both ulcerative colitis and Crohn's disease are a major public health problem with an etiology that has not been fully elucidated. There is a need to improve disease outcomes and preventive measures by developing new effective and lasting treatments. Although polyunsaturated fatty acid metabolites play an important role in the pathogenesis of several disorders, their contribution to IBD is yet to be understood. METHODS: Polyunsaturated fatty acids metabolite profiles were established from biopsy samples obtained from Crohn's disease, ulcerative colitis, or control patients. The impact of a prostaglandin I2 (PGI2) analog on intestinal epithelial permeability was tested in vitro using Caco-2 cells and ex vivo using human or mouse explants. In addition, mice were treated with PGI2 to observe dextran sulfate sodium (DSS)-induced colitis. Tight junction protein expression, subcellular location, and apoptosis were measured in the different models by immunohistochemistry and Western blotting. RESULTS: A significant reduction of PGI2 in IBD patient biopsies was identified. PGI2 treatment reduced colonic inflammation, increased occludin expression, decreased caspase-3 cleavage and intestinal permeability, and prevented colitis development in DSS-induced mice. Using colonic explants from mouse and human control subjects, the staurosporine-induced increase in paracellular permeability was prevented by PGI2. PGI2 also induced the membrane location of occludin and reduced the permeability observed in colonic biopsies from IBD patients. CONCLUSIONS: The present study identified a PGI2 defect in the intestinal mucosa of IBD patients and demonstrated its protective role during colitis.

The Expression of Anti-Müllerian Hormone Type II Receptor (AMHRII) in Non-Gynecological Solid Tumors Offers Potential for Broad Therapeutic Intervention in Cancer.

The anti-Müllerian hormone (AMH) belongs to the TGF-ß family and plays a key role during fetal sexual development. Various reports have described the expression of AMH type II receptor (AMHRII) in human gynecological cancers including ovarian tumors. According to qRT-PCR results confirmed by specific In-Situ Hybridization (ISH) experiments, AMHRII mRNA is expressed in an extremely restricted number of normal tissues. By performing ISH on tissue microarray of solid tumor samples AMHRII mRNA was unexpectedly detected in several non-gynecological primary cancers including lung, breast, head and neck, and colorectal cancers. AMHRII protein expression, evaluated by immunohistochemistry (IHC) was detected in approximately 70% of epithelial ovarian cancers. Using the same IHC protocol on more than 900 frozen samples covering 18 different cancer types we detected AMHRII expression in more than 50% of hepato-carcinomas, colorectal, lung, and renal cancer samples. AMHRII expression was not observed in neuroendocrine lung tumor samples nor in non-Hodgkin lymphoma samples. Complementary analyses by immunofluorescence and flow cytometry confirmed the detection of AMHRII on a panel of ovarian and colorectal cancers displaying comparable expression levels with mean values of 39,000 and 50,000 AMHRII receptors per cell, respectively. Overall, our results suggest that this embryonic receptor could be a suitable target for treating AMHRII-expressing tumors with an anti-AMHRII selective agent such as murlentamab, also named 3C23K or GM102. This potential therapeutic intervention was confirmed in vivo by showing antitumor activity of murlentamab against AMHRII-expressing colorectal cancer and hepatocarcinoma Patient-Derived tumor Xenografts (PDX) models.

The Caspase-1/IL-18 Axis of the Inflammasome in Tumor Cells: A Modulator of the Th1/Tc1 Response of Tumor-Infiltrating T Lymphocytes in Colorectal Cancer.

In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC.

Bariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells.

Glucagon-Like Peptide-1 (GLP-1) undergoes rapid inactivation by dipeptidyl peptidase-4 (DPP4) suggesting that target receptors may be activated by locally produced GLP-1. Here we describe GLP-1 positive cells in the rat and human stomach and found these cells co-expressing ghrelin or somatostatin and able to secrete active GLP-1 in the rats. In lean rats, a gastric load of glucose induces a rapid and parallel rise in GLP-1 levels in both the gastric and the portal veins. This rise in portal GLP-1 levels was abrogated in HFD obese rats but restored after vertical sleeve gastrectomy (VSG) surgery. Finally, obese rats and individuals operated on Roux-en-Y gastric bypass and SG display a new gastric mucosa phenotype with hyperplasia of the mucus neck cells concomitant with increased density of GLP-1 positive cells. This report brings to light the contribution of gastric GLP-1 expressing cells that undergo plasticity changes after bariatric surgeries, to circulating GLP-1 levels.

Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes.

BACKGROUND: Genome editing offers unique perspectives for optimizing the functional properties of T cells for adoptive cell transfer purposes. So far, PDCD1 editing has been successfully tested mainly in chimeric antigen receptor T (CAR-T) cells and human primary T cells. Nonetheless, for patients with solid tumors, the adoptive transfer of effector memory T cells specific for tumor antigens remains a relevant option, and the use of high avidity T cells deficient for programmed cell death-1 (PD-1) expression is susceptible to improve the therapeutic benefit of these treatments. METHODS: Here we used the transfection of CAS9/sgRNA ribonucleoproteic complexes to edit PDCD1 gene in human effector memory CD8+ T cells specific for the melanoma antigen Melan-A. We cloned edited T cell populations and validated PDCD1 editing through sequencing and cytometry in each T cell clone, together with T-cell receptor (TCR) chain's sequencing. We also performed whole transcriptomic analyses on wild-type (WT) and edited T cell clones. Finally, we documented in vitro and in vivo through adoptive transfer in NOD scid gamma (NSG) mice, the antitumor properties of WT and PD-1KO T cell clones, expressing the same TCR. RESULTS: Here we demonstrated the feasibility to edit PDCD1 gene in human effector memory melanoma-specific T lymphocytes. We showed that PD-1 expression was dramatically reduced or totally absent on PDCD1-edited T cell clones. Extensive characterization of a panel of T cell clones expressing the same TCR and exhibiting similar functional avidity demonstrated superior antitumor reactivity against a PD-L1 expressing melanoma cell line. Transcriptomic analysis revealed a downregulation of genes involved in proliferation and DNA replication in PD-1-deficient T cell clones, whereas genes involved in metabolism and cell signaling were upregulated. Finally, we documented the superior ability of PD-1-deficient T cells to significantly delay the growth of a PD-L1 expressing human melanoma tumor in an NSG mouse model. CONCLUSION: The use of such lymphocytes for adoptive cell transfer purposes, associated with other approaches modulating the tumor microenvironment, would be a promising alternative to improve immunotherapy efficacy in solid tumors.

The inhibitory receptor CD94/NKG2A on CD8+ tumor-infiltrating lymphocytes in colorectal cancer: a promising new druggable immune checkpoint in the context of HLAE/ß2m overexpression.

We previously demonstrated that HLA-E/ß2m overexpression by tumor cells in colorectal cancers is associated with an unfavorable prognosis. However, the expression of its specific receptor CD94/NKG2 by intraepithelial tumor-infiltrating lymphocytes, their exact phenotype and function, as well as the relation with the molecular status of colorectal cancer and prognosis remain unknown. Based on a retrospective cohort of 234 colorectal cancer patients, we assessed the expression of HLA-E, ß2m, CD94, CD8, and NKp46 by immunohistochemistry on tissue microarray. The expression profile of HLA-E/ß2m on tumor cells and the density of tumor-infiltrating lymphocytes were correlated to the clinicopathological and molecular features (Microsatellite status, BRAF and RAS mutations). Then, from the primary tumors of 27 prospective colorectal cancers, we characterized by multiparameter flow cytometry the nature (T and/or NK cells) and the co-expression of the inhibitory NKG2A or activating NKG2C chain of ex vivo isolated CD94+ tumor-infiltrating lymphocytes. Their biological function was determined using an in vitro redirected cytolytic activity assay. Our results showed that HLA-E/ß2m was preferentially overexpressed in microsatellite instable tumors compared with microsatellite stable ones (45% vs. 19%, respectively, p = 0.0001), irrespective of the RAS or BRAF mutational status. However, HLA-E/ß2m+ colorectal cancers were significantly enriched in CD94+ intraepithelial tumor-infiltrating lymphocytes in microsatellite instable as well as in microsatellite stable tumors. Those CD94+ tumor-infiltrating lymphocytes mostly corresponded to CD8+ αß T cells, and  to a lesser extent to NK cells, and mainly co-expressed a functional inhibitory NKG2A chain. Finally, a high number of CD94+ intraepithelial tumor-infiltrating lymphocytes in close contact with tumor cells was independently associated with a worse overall survival. In conclusion, these findings strongly suggest that HLA-E/ß2m-CD94/NKG2A represents a new druggable inhibitory immune checkpoint, preferentially expressed in microsatellite instable tumors, but also in a subgroup of microsatellite stable tumors, leading to a new opportunity in colorectal cancer immunotherapies.

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status.

Purpose: The recent success of anti-PD1 antibody in metastatic colorectal cancer (CRC) patients with microsatellite instability (MSI), known to be associated with an upregulated Th1/Tc1 gene signature, provides new promising therapeutic strategies. However, the partial objective response highlights a crucial need for relevant, easily evaluable, predictive biomarkers. Here we explore whether in situ assessment of Tbet+ tumor infiltrating lymphocytes (TILs) reflects a pre-existing functional antitumor Th1/Tc1/IFNγ response, in relation with clinicopathological features, microsatellite status and expression of immunoregulatory molecules (PD1, PDL1, IDO-1). Methodology: In two independent cohorts of CRC (retrospective n = 80; prospective n = 27) we assessed TILs density (CD3, Tbet, PD1) and expression profile of PDL1 and IDO-1 by immunohistochemistry/image analysis. Furthermore, the prospective cohort allowed to perform ex vivo CRC explant cultures and measure by Elisa the IFNγ response, at baseline and upon anti-PD1 treatment. Results: The density of Tbet+ TILs was significantly higher in MSI CRC, especially in the medullary subtype but also in a subgroup of MSS (microsatellite stable), and positively correlated with PD1 and PDL1 expression, but not with IDO-1. Finally, a high number of Tbet+ TILs was associated with a favorable overall survival. These Tbet+ TILs were functional as their density positively correlated with basal IFNγ levels. In addition, the combined score of Tbet+ PD1+ TILs coupled with IDO-1 expression predicted the magnitude of the IFNγ response upon anti-PD1. Conclusion: Altogether, immunohistochemical quantification of Tbet+ TILs is a reliable and accurate tool to recapitulate a preexisting Th1/Tc1/IFNγ antitumor response that can be reinvigorated by anti-PD1 treatment.

Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.

The gut-brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose-dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c-FOS-positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.-Jarry, A.-C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.-N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.

Roux-en-Y Gastric-Bypass and sleeve gastrectomy induces specific shifts of the gut microbiota without altering the metabolism of bile acids in the intestinal lumen.

Some shifts in the gut microbiota composition and its metabolic fingerprints have been associated to Sleeve gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB). So far, plasma bile acids have been associated with post-operative glucose improvement and weight loss, but nothing is known about their metabolism in the gut lumen. As bile acids are physiologically transformed by the microbiota into various species, the aim of this work was to study how SG and RYGB-associated dysbiosis impact the bioconversion of bile acids in the intestinal lumen. Comparing SHAM (n = 9) with our validated rat models of SG (n = 5) and RYGB (n = 6), we quantified luminal bile acids along the gut and found that the metabolic transformation of bile acids (deconjugation, dehydroxylation, and epimerization) is not different from the duodenum to the colon. However, in the cecum where the biotransformation mainly takes place, we observed deep alterations of the microbiota composition, which were specific of each type of surgery. In conclusion, despite specific dysbiosis after surgery, the bile acids metabolism in the gut lumen is highly preserved, suggesting that a resilience of the gut microbiota occurs after these procedures.

Intestinal plasticity in response to nutrition and gastrointestinal surgery.

The plasticity of a material corresponds to its capacity to change its feature under the effect of an external action. Intestinal plasticity could be defined as the ability of the intestine to modify its size or thickness and intestinal cells to modulate their absorption and secretion functions in response to external or internal cues/signals. This review will focus on intestinal adaptation mechanisms in response to diet and nutritional status. These physiological mechanisms allow a fine and rapid adaptation of the gut to promote absorption of ingested food, but they can also lead to obesity in response to overnutrition. This plasticity could thus become a therapeutic target to treat not only undernutrition but also obesity. How the intestine adapts in response to 2 types of surgical remodeling of the digestive tract-extensive bowel resection leading to intestinal failure and surgical treatment of pathological obesity (ie, bariatric surgeries)-will also be reviewed.

[The nurse, at the front line of the demand for care in the prison environment]. / L'infirmière, en première ligne de la demande de soins en milieu carcéral.

The specific nature of care in prisons requires that caregivers adapt it to the needs of the population in a particular context and environment. The prevalent pathologies of detainees guide health care missions towards actions of education and health promotion. In this context, the nursing role requires specific relational and technical skills related to general care, but also addictology, psychiatry and actions for health promotion and education.

The double stranded RNA analog poly-IC elicits both robust IFN-λ production and oncolytic activity in human gastrointestinal cancer cells.

PURPOSE: Type III IFN (IFN-λ) is the dominant frontline response over type I IFN in human normal intestinal epithelial cells upon viral infection, this response being mimicked by the dsRNA analog poly-IC. Poly-IC also induces cell death in murine intestinal crypts ex vivo. Here we examined whether these innate defense functions of normal intestinal epithelial cells are recapitulated in gastrointestinal carcinoma cells so that they could be harnessed to exert both immunoadjuvant and oncolytic functions, an unknown issue yet. EXPERIMENTAL DESIGN: Four human gastrointestinal carcinoma cell lines versus the Jurkat lymphoma cell line were used to assess the effects of intracellular poly-IC on i) IFN-λ secretion and cell proliferation and ii) role of NFκB signaling using the NFκB inhibitory peptide SN50 as a screening probe and a siRNA approach. RESULTS: Poly-IC induced in all cell lines except Jurkat both a robust IFN-λ secretion and a cytoreductive effect on adherent cells, restricted to proliferating cells and associated with cellular shedding and reduced clonogenicity of the shed cells. Collectively these findings demonstrate the oncolytic activity of poly-IC. Inhibiting NFκB in T84 cells using a siRNA approach decreased IFN-λ production without protecting the cells from the poly-IC oncolytic effects. In line with these findings IFN-λ, that upregulated the anti-viral protein MxA, was unable per se to alter T84 cell proliferation. CONCLUSION: Our demonstration that poly-IC-induced concomitant recapitulation of two innate functions of normal intestine, i.e. IFN-λ production and cell death, by human gastrointestinal cancer cells opens new perspectives in gastrointestinal cancer treatment.

[Physiopathological mechanisms of immune-related adverse events induced by anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies in cancer treatment]. / Mécanismes physiopathologiques des effets secondaires des immunothérapies par anticorps anti-CTLA-4, anti-PD-1 et anti-PD-L1 dans le traitement du cancer.

Recently, the emergence of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies called immune check-point inhibitors (ICPI) has modified the landscape of anti-cancer treatments. These therapeutics are associated with immune related adverse events that affect many organs, most commonly skin, digestive tract, endocrine glands and lungs. This review summarizes the main physiopathological hypotheses on the mechanisms of these toxicities. In most cases, the T lymphocytes hyperactivation induced by ICPI generates a specific response directed against tumor antigens, leading to anti-tumor activity in tumor tissues but also side effects in normal tisues called "on-target". The CD8+ cytotoxic T lymphocytes-mediated cell lysis induces the release of neoantigens, tumor antigens and auto-antigens from normal tissues, respectively. This phenomenon called "epitope spreading" leads to diversification of the T cell repertoire and thus to reduced immune tolerance, which is exacerbated by inhibition of regulator T lymphocytes. Furthermore, the predominant activation of Th1 and Th17T lymphocytes mediated by ICPI induced an increased production of pro-inflammatory cytokines such as interferon-γ (IFNγ) and interleukine-17 (IL-17). These two mechanisms are responsible for the so called "off-target" toxicities. The roles of cross-reactivity with the intestinal microbiota, hypersensitivity and the specific effect of PD-L2 remain to be determined. Better knowledge of these mechanisms will improve patient care and help predict patients at risk of developing severe toxicities to ICPIs.

Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome.

The extent to which microbiota alterations define or influence the outcome of metabolic diseases is still unclear, but the byproducts of microbiota metabolism are known to have an important role in mediating the host-microbiota interaction. Here, we identify that in both pre-clinical and clinical settings, metabolic syndrome is associated with the reduced capacity of the microbiota to metabolize tryptophan into derivatives that are able to activate the aryl hydrocarbon receptor. This alteration is not merely an effect of the disease as supplementation with AhR agonist or a Lactobacillus strain, with a high AhR ligand-production capacity, leads to improvement of both dietary- and genetic-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis, through improvement of intestinal barrier function and secretion of the incretin hormone GLP-1. These results highlight the role of gut microbiota-derived metabolites as a biomarker and as a basis for novel preventative or therapeutic interventions for metabolic disorders.