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
DOI:
10.1126/science.abo2296
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
Bookmarklink
