Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells

Matas-Rico, Elisa; Frijlink, Elselien; Àvila, Irene van der Haar; Menegakis, Apostolos; Zon, Maaike van; Morris, Andrew J.; Koster, Jan; Salgado-Polo, Fernando; Kivit, Sander de; Lança, Telma; Mazzocca, Antonio; Johnson, Zoë; Haanen, John B.A.G.; Schumacher, Ton N.; Perrakis, Anastassis; Verbrugge, Inge; Berg, Joost H. van den; Borst, Jannie; Moolenaar, Wouter H.

doi:10.1016/j.celrep.2021.110013

Cited by 48 publications

(45 citation statements)

References 75 publications

(116 reference statements)

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“…However, applications in liver disease ( 54 , 55 , 56 ) and pancreatic cancer ( https://www.ionctura.com/admin/resources/ioa-289sitc-results-9-11final.pdf ) are pursued. More recently, ATX has been shown to be chemorepulsive for tumor-infiltrating lymphocytes and circulating CD8 + T cells ex vivo and to suppress tumor infiltration of cytotoxic CD8 + T cells in an anticancer vaccination model, suggesting new therapeutic opportunities in cancer ( 57 ).…”

Section: Substrate Specificity and Catalytic Mechanismmentioning

confidence: 99%

“…ATX was identified as an “autocrine motility factor” for melanoma cells in the early 1990s ( 72 ), but it took another 10 years before it was uncovered as a lysoPLD present in serum and plasma. Recent studies on ATX-mediated T-cell migration and immune evasion ( 57 ) point to ATX as a dual-function protein that both produces and chaperones LPA for local delivery of LPA to its cognate receptors when ATX interacts with adhesive molecules ( 13 , 73 ).…”

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

“…In the adult, ATX shows its highest expression in the brain, fibroblasts, and lymph nodes. Based on animal studies, the ATX-LPA signaling axis has been linked to T-cell migration, wound healing, inflammation, tissue fibrosis, tumor progression and immune evasion ( 57 , 76 , 77 , 78 , 79 , 80 ). ATX is highly expressed in most solid tumors, in part attributable to ATX-expressing stromal cells such as cancer-associated fibroblasts ( 57 ); however, cancer-associated mutations or deletions in ENPP2 have not been documented to date.…”

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

“…Based on animal studies, the ATX-LPA signaling axis has been linked to T-cell migration, wound healing, inflammation, tissue fibrosis, tumor progression and immune evasion ( 57 , 76 , 77 , 78 , 79 , 80 ). ATX is highly expressed in most solid tumors, in part attributable to ATX-expressing stromal cells such as cancer-associated fibroblasts ( 57 ); however, cancer-associated mutations or deletions in ENPP2 have not been documented to date. In the nervous system, LPA signaling has been associated with neuropathic pain, cerebral ischemia, brain and spinal cord injury, as well as neurodegenerative diseases ( 81 ).…”

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

“…Finally, recent studies have revealed an unexpected role for ATX secreted by tumor cells, namely as a chemorepellent for CD8 + T cells, both in vitro and in tumor-bearing mice. ATX appears to repel T cells via the LPA 6 receptor (LPAR6), notably independently of extracellular LPA levels ( 57 ). Consequently, pharmacological inhibition of ENPP2/ATX should stimulate T-cell infiltration into tumors, thereby enhancing the efficacy of immunotherapy, a scenario that warrants further studies.…”

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

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Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity

Borza

Salgado-Polo

Moolenaar

et al. 2022

Journal of Biological Chemistry

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Ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family members (ENPP1–7) have been implicated in key biological and pathophysiological processes, including nucleotide and phospholipid signaling, bone mineralization, fibrotic diseases, and tumor-associated immune cell infiltration. ENPPs are single-pass transmembrane ecto-enzymes, with notable exceptions of ENPP2 (Autotaxin) and ENNP6, which are secreted and glycosylphosphatidylinositol (GPI)-anchored, respectively. ENNP1 and ENNP2 are the best characterized and functionally the most interesting members. Here, we review the structural features of ENPP1–7 to understand how they evolved to accommodate specific substrates and mediate different biological activities. ENPPs are defined by a conserved phosphodiesterase (PDE) domain. In ENPP1–3, the PDE domain is flanked by two N-terminal somatomedin B-like domains and a C-terminal inactive nuclease domain that confers structural stability, whereas ENPP4–7 only possess the PDE domain. Structural differences in the substrate-binding site endow each protein with unique characteristics. Thus, ENPP1, ENPP3, ENPP4, and ENPP5 hydrolyze nucleotides, whereas ENPP2, ENPP6, and ENNP7 evolved as phospholipases through adaptions in the catalytic domain. These adaptations explain the different biological and pathophysiological functions of individual members. Understanding the ENPP members as a whole advances our insights into common mechanisms, highlights their functional diversity, and helps to explore new biological roles.

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Section: Substrate Specificity and Catalytic Mechanismmentioning

confidence: 99%

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

Section: Enpps In Physiology and Diseasementioning

confidence: 99%

See 3 more Smart Citations

Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity

Borza

Salgado-Polo

Moolenaar

et al. 2022

Journal of Biological Chemistry

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A 24‐Week, Phase IIa, Randomized, Double‐Blind, Placebo‐Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis

Khanna

Denton

Fürst

et al. 2023

Arthritis & Rheumatology

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Objective We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). Methods NOVESA was a 24‐week, multicenter, phase IIa, double‐blind, placebo‐controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104‐week open‐label extension (OLE). Results Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (–8.9 versus –6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment‐related treatment‐emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. Conclusion Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477.

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Lysophosphatidic acid promotes ESCC progression by increasing the level of CCL2 secreted by esophageal epithelial cells

Ma,

et al. 2024

The Journal of Gene Medicine

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BackgroundLysophosphatidic acid (LPA) is a small bioactive lipid which acts as a potent regulator in various tumor progressions through six G‐protein‐coupled receptors (LPA1–LPA6). Our previous study demonstrated that the LPA‐producing enzyme, autotaxin (ATX), was upregulated in esophageal squamous cell carcinoma (ESCC) and ATX high expression levels indicated a poor prognosis. Esophageal squamous cell carcinoma is a type of malignant tumor which originates from epithelial cells. Its progression can be affected by the interaction between cancer cells and normal cells. However, the impact of LPA on the interaction between esophageal epithelial cells and cancer cells in the development of ESCC remains uncertain.MethodsMTS and Edu assays were performed to determine ESCC cell proliferation in culture medium (CM) derived from LPA‐stimulated esophageal epithelial cells (Het‐1a). A wound healing assay, transwell migration and an invasion assay were performed to assess the metastatic ability of ESCC cells. Cytokine array analysis was conducted to detect the differentially secreted cytokines in CM. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to uncover the pathways and cytokines that are influenced by LPA in ESCC. Immunohistochemical staining was employed to measure the expression of ATX and CCL2 in early‐stage ESCC. Quantitative real‐time PCR, western blot, enzyme‐linked immunosorbent assay and an antibody neutralization assay were employed to measure the mechanism of LPA‐mediated communication between epithelial cells and cancer cells.ResultsFunctional experiments showed that exposing ESCC cancer cells to CM from LPA‐treated Het‐1a results in promoting proliferation, migration, invasion and epithelial–mesenchymal transition processes. Using cytokine array analysis, we discovered that LPA triggers the release of multiple cytokines from epithelial cells. After screening of the TCGA and GEO databases, CCL2 was identified and found to be correlated with ATX expression in ESCC. Furthermore, CCL2 levels in both mRNA expression and secretion were observed to be upregulated in epithelial cells upon stimulation with LPA. Blocking CCL2 effectively reduced the pro‐migration influence of CM derived from LPA‐treated Het‐1a. Mechanism studies have demonstrated that LPA activated the NF‐κB signaling pathway through LPA1/3, ultimately causing an increase in CCL2 expression and secretion in Het‐1a.ConclusionsOur findings, taken together, demonstrate that CM from LPA‐treated esophageal epithelial cells plays a significant role in promoting the progression of ESCC, with CCL2 acting as the primary regulator.

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Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells

Cited by 48 publications

References 75 publications

Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity

Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity

A 24‐Week, Phase IIa, Randomized, Double‐Blind, Placebo‐Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis

Lysophosphatidic acid promotes ESCC progression by increasing the level of CCL2 secreted by esophageal epithelial cells

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