An autophagy program that promotes T cell egress from the lymph node controls responses to immune checkpoint blockade

Lymphatic endothelial cells (LECs) of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs c...

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Vydáno v:	Cell reports (Cambridge) Ročník 43; číslo 4; s. 114020
Hlavní autoři:	Houbaert, Diede, Nikolakopoulos, Apostolos Panagiotis, Jacobs, Kathryn A., Meçe, Odeta, Roels, Jana, Shankar, Gautam, Agrawal, Madhur, More, Sanket, Ganne, Maarten, Rillaerts, Kristine, Boon, Louis, Swoboda, Magdalena, Nobis, Max, Mourao, Larissa, Bosisio, Francesca, Vandamme, Niels, Bergers, Gabriele, Scheele, Colinda L.G.J., Agostinis, Patrizia
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 23.04.2024 Elsevier
Témata:	Animals autophagy Autophagy - drug effects Autophagy-Related Protein 5 - genetics Autophagy-Related Protein 5 - metabolism cancer Cell Movement CP: Cancer CP: Immunology Endothelial Cells - metabolism Humans Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use immunotherapy Immunotherapy - methods lymph node Lymph Nodes - immunology lymphatic endothelial cells Lysophospholipids - metabolism Mice Mice, Inbred C57BL Sphingosine - analogs & derivatives Sphingosine - metabolism Sphingosine - pharmacology T cell trafficking T-Lymphocytes - immunology T-Lymphocytes - metabolism CP: Immunology autophagy lymph node CP: Cancer immunotherapy lymphatic endothelial cells cancer T cell trafficking
ISSN:	2211-1247, 2211-1247
On-line přístup:	Získat plný text
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Shrnutí:	Lymphatic endothelial cells (LECs) of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs control T cell dynamics under steady-state and tumor-bearing conditions is lacking. Intravital imaging combined with immune phenotyping shows that LEC-specific deletion of the essential autophagy gene Atg5 alters intranodal positioning of lymphocytes and accrues their persistence in the LNs by increasing the availability of the main egress signal sphingosine-1-phosphate. Single-cell RNA sequencing of tumor-draining LNs shows that loss of ATG5 remodels niche-specific LEC phenotypes involved in molecular pathways regulating lymphocyte trafficking and LEC-T cell interactions. Functionally, loss of LEC autophagy prevents recruitment of tumor-infiltrating T and natural killer cells and abrogates response to immunotherapy. Thus, an LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics. [Display omitted] •Thwarting LEC autophagy prevents lymphocyte egress from the lymph node (LN)•LEC autophagy governs the S1P gradient and the intranodal dynamics of T and NK cells•Loss of LEC autophagy remodels niche-specific LEC phenotypes in tumor-draining LNs•LEC-autophagy blockade blunts efficacy of ICBs by sequestering T and NK cells in the LNs Houbaert et al. find that defective autophagy in lymphatic endothelial cells (LECs) prevents lymphocyte’s egress from lymph nodes. In tumor-bearing mice, LEC autophagy endorses the recruitment of peripheral T and NK cells to the tumor and ICB-driven antitumor immunity, further underscoring the lymph nodes as critical players in immunotherapy responses.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2024.114020