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  • 1
    Online Resource
    Online Resource
    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
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    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
    detail.hit.zdb_id: 2005181-5
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