Biology subjects

Houbaert, D.

Publications and source records attributed to Houbaert, D..

3 recordsLinked to original sources

bioRxiv2026

Autophagy in lymphatic endothelial cells promotes lung metastasis

Macroautophagy/autophagy is the main lysosomal pathway for the degradation and recycling of cytoplasmic cargo, with emerging roles in endothelial cell (EC) biology. While autophagy has been extensively studied in blood ECs, its function in lymphatic ECs (LECs) remains unexplored. Given the central role of the lymphatic system in antitumor immunity and metastatic spread, we investigated how LEC autophagy affects metastatic lung colonization. In line with previous reports showing that autophagy regulates the availability of the egress signal sphingosine 1 phosphate (S1P) in secondary lymphoid organs (SLOs), lungs of non-tumor-bearing mice with LEC-specific genetic deletion of Atg5 (ATG5LEC-KO mice) exhibited reduced lymphocyte infiltration. Remarkably, in tumor-bearing mice, either genetic loss of LEC-autophagy or pharmacological blockade of S1P lyase by 4-deoxypyridoxine (DOP) suppressed lung metastasis. Pulmonary immune profiling revealed that while DOP enhanced effector T cell activity despite lower numbers, LEC-autophagy-deficient mice markedly increased the B and CD8 T Cell abundance coupled with profound reduction of VEGFR3 expression in the lung lymphatic vasculature. Together, these findings uncover an autophagy-dependent remodeling of the lymphatic routes and immune niches that fosters metastatic seeding and growth in the lung.

cancer biology↗

bioRxiv2023

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

Lymphatic endothelial cells (LECs) lining the lymphatic vessels 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. Using intravital and high-resolution imaging combined with immune phenotyping, we show 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 S1P. Single-cell RNA-sequencing of tumor-draining LNs from WT and ATG5LEC-KO mice unveils 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 cells and NK cells and abrogates tumor regression in response to anti-PD-1 or anti-CTLA4-based immunotherapy. Thus, a unique LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/549282v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1a4bfe1org.highwire.dtl.DTLVardef@1317fe2org.highwire.dtl.DTLVardef@c2fa20org.highwire.dtl.DTLVardef@b35dba_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

TUMOR ENDOTHELIAL CELL AUTOPHAGY IS A KEY VASCULAR-IMMUNE CHECKPOINT IN MELANOMA

Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh/AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy. Congruently, patients responding to immunotherapy exhibit an increased presence of inflamed vessels, interfacing with infiltrating CD8+ T cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, autophagy is a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.

cancer biology↗