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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Published in:Cell reports (Cambridge) Vol. 43; no. 4; p. 114020
Main Authors: 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
Format: Journal Article
Language:English
Published: United States Elsevier Inc 23.04.2024
Elsevier
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2024.114020