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

ABSTRACT: 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 Gα_12/13-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.

SUBMITTER: Matas-Rico E

PROVIDER: S-EPMC8761359 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8<sup>+</sup> T cells.

Matas-Rico Elisa E Frijlink Elselien E van der Haar Àvila Irene I Menegakis Apostolos A van Zon Maaike M Morris Andrew J AJ Koster Jan J Salgado-Polo Fernando F de Kivit Sander S Lança Telma T Mazzocca Antonio A Johnson Zoë Z Haanen John J Schumacher Ton N TN Perrakis Anastassis A Verbrugge Inge I van den Berg Joost H JH Borst Jannie J Moolenaar Wouter H WH

Cell reports 20211101 7

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<sup>+</sup> T cells ex vivo, with ATX functioning as ...[more]

PMID: 34788605

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Project description:BackgroundLung cancer remains one of the most prevalent cancer types worldwide, with a high mortality rate. Upregulation of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) may represent a key mechanism for evading immune surveillance. Immune checkpoint blockade (ICB) antibodies against PD-1 or PD-L1 are therefore widely used to treat patients with lung cancer. However, the mechanisms by which lung cancer and neutrophils in the microenvironment sustain PD-L1 expression and impart stronger inhibition of CD8+ T cell function remain unclear.MethodsWe investigated the role and underlying mechanism by which PD-L1+ lung cancer and PD-L1+ neutrophils impede the function of CD8+ T cells through magnetic bead cell sorting, quantitative real-time polymerase chain reaction (RT-PCR), western blotting, enzyme-linked immunosorbent assays, confocal immunofluorescence, gene silencing, flow cytometry, etc. In vivo efficacy and safety studies were conducted using (Non-obeseDiabetes/severe combined immune deficiency) SCID/NOD mice. Additionally, we collected clinical and prognostic data from 208 patients who underwent curative lung cancer resection between 2017 and 2018.ResultsWe demonstrated that C-X-C motif chemokine ligand 5 (CXCL5) is markedly overexpressed in lung cancer cells and is positively correlated with a poor prognosis in patients with lung cancer. Mechanistically, CXCL5 activates the phosphorylation of the Paxillin/AKT signaling cascade, leading to upregulation of PD-L1 expression and the formation of a positive feedback loop. Moreover, CXCL5 attracts neutrophils, compromising CD8+ T cell-dependent antitumor immunity. These PD-L1+ neutrophils aggravate CD8+ T cell exhaustion following lung cancer domestication. Combined treatment with anti-CXCL5 and anti-PD-L1 antibodies significantly inhibits tumor growth in vivo.ConclusionsOur findings collectively demonstrate that CXCL5 promotes immune escape through PD-L1 upregulation in lung cancer and neutrophils chemotaxis through autocrine and paracrine mechanisms. CXCL5 may serve as a potential therapeutic target in synergy with ICBs in lung cancer immunotherapy.

Project description:BackgroundAlthough tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer.MethodsTo evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A's function. In a translational approach, we validated activin-A's anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients.ResultsAdministration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells.ConclusionsIn this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

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

Publications

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8<sup>+</sup> T cells.

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

Publications

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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