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Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8(+) T cells
- Source :
- Cell Reports, 37(7). CELL PRESS, Cell reports, 37(7):110013. Cell Press, Cell Reports, Vol 37, Iss 7, Pp 110013-(2021), Cell reports
- Publication Year :
- 2021
-
Abstract
- SUMMARY Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1–6. ATX/LPA promotes tumor cell migration and metastasis via LPAR1 and T cell motility via LPAR2, yet its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) and circulating CD8+ T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T cell repulsion predominantly involves Gα12/13-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor regression. Moreover, single-cell data from melanoma tumors are consistent with intratumoral ATX acting as a T cell repellent. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities.<br />In brief Through LPA production, ATX modulates the tumor microenvironment in autocrine-paracrine manners. Matas-Rico et al. show that ATX/LPA is chemorepulsive for T cells with a dominant inhibitory role for Gα12/13-coupled LPAR6. Upon anticancer vaccination, tumor-intrinsic ATX suppresses the infiltration of CD8+ T cells without affecting their cytotoxic quality.<br />Graphical Abstract
- Subjects :
- autotaxin
Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings]
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings]
medicine.medical_treatment
Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Movement::Chemotaxis [Medical Subject Headings]
CD8-Positive T-Lymphocytes
Receptores acoplados a proteínas G
Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Lysophospholipid::Receptors, Lysophosphatidic Acid [Medical Subject Headings]
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings]
Mice
chemistry.chemical_compound
G protein-coupled receptors
Neoplasms
Lysophosphatidic acid
Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::Lymphocytes, Tumor-Infiltrating [Medical Subject Headings]
Organisms::Eukaryota::Animals [Medical Subject Headings]
Cytotoxic T cell
Receptors, Lysophosphatidic Acid
Biology (General)
Melanoma
Chemistry
Chemotaxis
anti-cancer vaccination
Linfocitos T
Neoplasias
Chemorepulsion
Autotaxin
Tumor microenvironment
single-cell RNAseq
Chemicals and Drugs::Lipids::Membrane Lipids::Phospholipids::Glycerophosphates::Phosphatidic Acids::Lysophospholipids [Medical Subject Headings]
Female
immunotherapy
Immunotherapy
Signal Transduction
QH301-705.5
T cells
chemorepulsion
Anti-cancer vaccination
Article
General Biochemistry, Genetics and Molecular Biology
Single-cell RNAseq
Lymphocytes, Tumor-Infiltrating
Células
Microambiente tumoral
Cell Line, Tumor
medicine
melanoma
Animals
Humans
tumor microenvironment
Inmunoterapia
LPAR2
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings]
LPAR1
Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunization::Immunotherapy, Active::Vaccination [Medical Subject Headings]
Phosphoric Diester Hydrolases
Phenomena and Processes::Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironment [Medical Subject Headings]
Iysophosphatidic acid
Mice, Inbred C57BL
Cancer research
Lysophospholipids
lysophosphatidic acid
Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes::CD8-Positive T-Lymphocytes [Medical Subject Headings]
Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Phosphoric Diester Hydrolases [Medical Subject Headings]
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Database :
- OpenAIRE
- Journal :
- Cell Reports, 37(7). CELL PRESS, Cell reports, 37(7):110013. Cell Press, Cell Reports, Vol 37, Iss 7, Pp 110013-(2021), Cell reports
- Accession number :
- edsair.doi.dedup.....f76b9a7073f697d72868dba203452394