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  • 1
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    A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6649 ( 2023-06-09)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6649 ( 2023-06-09)
    Abstract: Resistance of cancers to immune checkpoint inhibitors (ICIs) can result from antibiotic (ABX) treatment, likely as a result of a deviated gut microbiota. ABX compromise clinical outcome when administered before, rather than during, ICI administration, suggesting that bacterial recolonization following ABX discontinuation may be deleterious. Gut commensals induce the differentiation of an immunosuppressive subset of FoxP3 + retinoic acid receptor–related orphan receptor-γt (RORγt + ) regulatory (T reg 17) cells. Lymphocytes primed in the mesenteric lymph nodes (mLNs) or homing to the intestinal lamina propria express the α4β7 integrin interacting with its counter-receptor, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed in high endothelial venules (HEVs). RATIONALE We hypothesized that disruption of the MAdCAM-1–α4β7 interaction that retains T reg 17 cells might cause their migration from the gut to tumors and thereby compromise the anticancer effects of ICIs. We used two complementary methods to visualize the exodus of intestinal T cells to subcutaneous tumors and tumor-draining lymph nodes (tdLNs): (i) Kaede mice expressing a fluorescent protein that is photoconverted upon ultraviolet light illumination of the ileum and (ii) the injection of carboxyfluorescein succinimidyl ester into mLNs. Moreover, we used transgene-enforced Madcam1 expression in the liver to locally intercept T reg 17 cells during their migration. RESULTS Several classes of ABX down-regulated Madcam1 expression in ileal venules, Peyer’s patches and mLNs, coinciding with the ileal exodus of α4β7 + T helper (T h 17) and T reg 17 cells toward extraintestinal tumors and tdLNs. This ABX-induced reduction in MAdCAM-1 could be explained by the recolonization of the gut by the genus Enterocloster (encompassing the E. clostridioformis species), because its oral administration was sufficient to down-regulate MAdCAM-1 expression through its effects on bile acid metabolism. Genetic or antibody-mediated neutralization of MAdCAM-1 or α4β7 integrin phenocopied the immunosuppressive effects of ABX, promoting resistance to ICIs targeting programmed cell death protein 1 (PD-1) and inducing a surge in gut-derived α4β7 + T reg 17 cells in tdLNs and tumors. Restoration of MAdCAM-1 on ileal HEV by fecal microbial transplantation or blockade of IL-17A reversed the inhibitory effects of ABX. Ectopic expression of MAdCAM-1 in the liver caused the local retention of enterotropic α4β7 + T reg 17 cells, reducing their accumulation in tumor beds and improving immunotherapy outcomes in mice. Finally, low-serum-soluble MAdCAM-1 was identified as a proxy of intestinal dysbiosis and a robust predictor of shorter overall and progression-free survival of renal, bladder, and lung cancer patients under immunotherapy with antibodies targeting PD-1 or PD-L1. In non-small-cell lung cancer patients, the prognostic value of soluble MAdCAM-1 was independent of PD-L1 expression. CONCLUSION The relocation of enterotropic and immunosuppressive T reg 17 cells to cancerous tissue (tumors and tdLNs) is repressed by the molecular interaction between the HEV addressin MAdCAM-1 and the integrin α4β7 expressed by T reg 17 cells. Disruption of the MAdCAM-1 expression by ABX or gut dysbiosis causes the relocation of T reg 17 cells into tumors, consequently compromising cancer immunosurveillance and the therapeutic efficiency of ICIs in mice and patients. MAdCAM-1 as a gut immune checkpoint for cancer immunosurveillance. Bacteria from the genus Enterocloster , for example, after discontinuation of ABX, induce the down-regulation of MAdCAM-1 in the ileal lamina propria and mLNs, inducing the exodus of the immunosuppressive α4β7 + T reg 17 cells from the gut to cancers and tdLNs. Disruption of the MAdCAM-1–α4β7 axis compromises the efficacy of immunotherapy in mice and patients.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abo2296
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 2
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    Guidelines for DC preparation and flow cytometry analysis of mouse nonlymphoid tissues
    Wiley ; 2022
    In:  European Journal of Immunology
    Details
    In: European Journal of Immunology, Wiley
    Abstract: This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state‐of‐the‐art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various nonlymphoid tissues. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single‐cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in‐depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer‐reviewed by leading experts and approved by all coauthors, making it an essential resource for basic and clinical DC immunologists.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Article
    DOI: 10.1002/eji.202249819
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 3
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    The Lung Immune Prognostic Index (LIPI) stratifies prognostic groups and correlates with gut microbiota (GM) in patients with advanced renal cell carcinoma (RCC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. 719-719
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 719-719
    Abstract: 719 Background: The LIPI score has been reported as an independent prognostic factor in RCC patients treated with immune checkpoint inhibitors (ICI) or tyrosine kinase inhibitors (TKI). Here, we aimed to correlate LIPI score and GM composition in patients with RCC. Methods: We prospectively collected fecal samples of all comers RCC patients who started a 1 st or beyond line therapy (standard or clinical trial) in the NCT0457446 at Gustave Roussy. Neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were obtained from routine blood tests. Shot gun metagenomic sequencing (MGS) data were analyzed by multivariate and pair-wise/fold ratio . Clinical benefit ratio (CBR, complete response + partial response + stable disease, RECIST1.1) and overall survival (OS, from treatment start) were evaluated. Multivariate analysis (MVA) for OS included age, gender, therapy line, IMDC, histology, hypoalbuminemia. Results: From February 2016 to July 2021, 160 patients were screened and 102 were included. Median age was 61 years (22-89), patients were mostly males (75%) and clear cell histology (90%). Patients were treated in 1 st (15%), 2 nd (53%) and beyond (32%) lines. Treated with ICI monotherapy (65%), followed by TKI or mTOR (20%) and ICI combination (19%). IMDC was 32% good (G), 54% intermediate (I) and 14% poor (P) and LIPI was 69% G, 25% I and 6% P. Median OS was 42.9, 17.7 and 8.3 months in patients with LIPI G, I and P, respectively (p 〈 0.0001) . Among IMDC risk groups, IMDC G + LIPI G had better OS compared to other subgroups (p=0.017), and those with IMDC P + LIPI P had the worse OS. Overall, LIPI G had higher rates of CBR than I+P LIPI (74% vs 50%; p=0.0158). At MVA, LIPI was independently associated with OS (HR 6.25, 2.02-24.34; p=0.0187). Overall, Parabacteroides merdae and Veillonella parvula were enriched in LIPI I+P, while LIPI G harbored Faecalibacterium prausnitzii. In patients treated with ICI monotherapy, LIPI I+P were enriched with Bacteroides spp ( P. merdae, Phocaeicola vulgatus), and LIPI G had an overrepresentation of Ruminococcaceae unclass bacterium. Conclusions: We report the first MGS study correlating LIPI score and GM composition in RCC patients. LIPI score correlates with clinical outcomes (OS and CBR) and helped to better-stratified IMDC risk groups. Patients LIPI G harbor health-related commensals, while I and P groups are associated with harmful ones. LIPI score could represent a clinically relevant score to stratify mRCC patients. Clinical trial information: NCT04567446 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.719
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
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    Le Double Cursus Santé Sciences à l’UFR Santé de Rouen : États des lieux et perspectives
    EDP Sciences ; 2022
    In:  médecine/sciences Vol. 38, No. 8-9 ( 2022-08), p. 698-706
    Details
    In: médecine/sciences, EDP Sciences, Vol. 38, No. 8-9 ( 2022-08), p. 698-706
    Abstract: The Double degree in Health and Sciences (DCSS) provides an early training in research for future healthcare professionals. The profound transformation of the healthcare system and the advent of new analytical and digital technologies highlight the urgent need to link research to clinical practice. At the international level, especially in the United States, these programs point out the key role of healthcare professionals with both medical and scientific expertise. In France, a DCSS during medical studies was set up in the 2000’s. This training is still heterogeneous and is not organized in all Faculties of Health Sciences. The Rouen Faculty of Health Sciences observed in 2016 that the number of students involved in DCSS was very low or even zero, depending on the year. The Rouen Faculty of Health Sciences initiated an institutional support in 2017 that led to the creation of a student mentorship dedicated to DCSS. This mentorship and the institutional leaders of this course have initiated a theoretical and practical training program. The organization of the DCSS of the Rouen Faculty of Health Sciences and the creation of a student mentorship program enabled us to increase the number of candidates interested in the DCSS (from 2 in 2016 to 26 in 2021) and to obtain an institutional recognition of this double major.
    Type of Medium: Online Resource
    ISSN: 0767-0974 , 1958-5381
    URL: Article
    DOI: 10.1051/medsci/2022106
    Language: French
    Publisher: EDP Sciences
    Publication Date: 2022
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  • 5
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    Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery Vol. 12, No. 4 ( 2022-04-01), p. 1128-1151
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 12, No. 4 ( 2022-04-01), p. 1128-1151
    Abstract: Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies. Significance: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-21-0999
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery Vol. 12, No. 4 ( 2022-04-01), p. 958-983
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 12, No. 4 ( 2022-04-01), p. 958-983
    Abstract: Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants. Significance: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-21-1441
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis
    Springer Science and Business Media LLC ; 2021
    In:  Cell Death & Differentiation Vol. 28, No. 12 ( 2021-12), p. 3297-3315
    Details
    In: Cell Death & Differentiation, Springer Science and Business Media LLC, Vol. 28, No. 12 ( 2021-12), p. 3297-3315
    Abstract: Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus–host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B + FasL + , Eomes high TCF-1 high , PD-1 + CD8 + Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.
    Type of Medium: Online Resource
    ISSN: 1350-9047 , 1476-5403
    URL: Article
    DOI: 10.1038/s41418-021-00817-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 8
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    Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4548-4548
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4548-4548
    Abstract: 4548 Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed to assess the prognostic impact of MAdCAM-1 in ICI-treated mRCC pts. Methods: The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) is a multicentric study that assessed the activity and safety of Nivolumab in pts with clear cell mRCC after anti-angiogenic therapy. We measured serum soluble MAdCAM-1 (sMAdCAM-1) levels (correlating ileal MAdCAM-1 transcripts) using Human Luminex Discovery Assay in the available plasma. Progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) were assessed using sMAdCAM-1 median as a cut off value (high if 〉 median and low if 〈 median). Multivariate Cox analysis adjusted for established risk factors: ATB, gender, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis. Two independent cohorts of metastatic lung and bladder cancer patients validated the data. Results: Overall, 212 pts were included. Median age was 64 years (22-87), and pts were mostly male (82%). ATB users had lower levels of sMadCAM-1. Low sMadCAM-1 pts had diminished OS compared to high sMadCAM-1 pts [HR 2.97 (95%CI 1.99-4.44), p 〈 .0001]: 13.3 (95%CI 9.8-14.9; 72/106) versus 25.3 (95%CI 24.1-NR; 36/106) months. Also, low sMadCAM-1 pts had diminished PFS [HR 1.92 (1.43-2.57), p 〈 .0001]: 2.6 (95%CI 2.4-2.8; 99/106) versus 5.2 (95%CI 4.6-5.7; 86/106) months. Interestingly, sMAdCAM-1 was independently associated with OS [HR 2.40 (1.52-3.80), p=0.0002] and PFS [HR 1.55 (1.13-2.13), p=0.0071] in multivariate analysis. Low sMadCAM-1 pts had lower CBR (37% versus 63%, p=0.0004). Serum sMAdCAM-1 also predicted OS in 381 ICI-treated patients with lung and bladder cancer. Conclusions: Low sMAdCAM-1 is associated with ATB intake, ATB-independent gut dysbiosis and worse outcomes, in ICI-treated pts with metastatic lung, bladder and RCC cancer. ELISA determination of sMAdCAM-1 might guide the selection of patients amenable to microbiota-center ed interventions, such as Akkermansia sp., and fecal microbiota transplantation. Clinical trial information: NCT0301335 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4548
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 9
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    RBD- specific Th1 responses are associated with vaccine-induced protection against SARS-CoV-2 infection in patients with hematological malignancies
    Informa UK Limited ; 2023
    In:  OncoImmunology Vol. 12, No. 1 ( 2023-12-31)
    Details
    In: OncoImmunology, Informa UK Limited, Vol. 12, No. 1 ( 2023-12-31)
    Type of Medium: Online Resource
    ISSN: 2162-402X
    URL: Article
    DOI: 10.1080/2162402X.2022.2163785
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2023
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  • 10
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    Immune responses during COVID-19 infection
    Informa UK Limited ; 2020
    In:  OncoImmunology Vol. 9, No. 1 ( 2020-01)
    Details
    In: OncoImmunology, Informa UK Limited, Vol. 9, No. 1 ( 2020-01)
    Type of Medium: Online Resource
    ISSN: 2162-402X
    URL: Article
    DOI: 10.1080/2162402X.2020.1807836
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2020
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