1. Cancer Biology
  2. Immunology and Inflammation

Human primed ILCPs support endothelial activation through NF-κB signaling

  1. Giulia Vanoni
  2. Giuseppe Ercolano
  3. Simona Candiani
  4. Mariangela Rutigliani
  5. Mariangela Lanata
  6. Laurent Derré
  7. Emanuela Marcenaro
  8. Pascal Schneider
  9. Pedro Romero
  10. Camilla Jandus  Is a corresponding author
  11. Sara Trabanelli  Is a corresponding author
  1. University of Lausanne - Ludwig Institute for Cancer Research, Switzerland
  2. University of Geneva, Switzerland
  3. University of Genova, Italy
  4. E.O. Galliera Hospital, Italy
  5. University Hospital of Lausanne (CHUV), Switzerland
  6. University of Lausanne, Switzerland
https://doi.org/10.7554/eLife.58838
Share this article
Cite this article
  1. Giulia Vanoni
  2. Giuseppe Ercolano
  3. Simona Candiani
  4. Mariangela Rutigliani
  5. Mariangela Lanata
  6. Laurent Derré
  7. Emanuela Marcenaro
  8. Pascal Schneider
  9. Pedro Romero
  10. Camilla Jandus
  11. Sara Trabanelli
(2021)
Human primed ILCPs support endothelial activation through NF-κB signaling
eLife 10:e58838.
https://doi.org/10.7554/eLife.58838
  2. Download BibTeX
  3. Download .RIS

Abstract

Innate lymphoid cells (ILCs) represent the most recently identified subset of effector lymphocytes, with key roles in the orchestration of early immune responses. Despite their established involvement in the pathogenesis of many inflammatory disorders, the role of ILCs in cancer remains poorly defined. Here we assessed whether human ILCs can actively interact with the endothelium to promote tumor growth control, favoring immune cell adhesion. We show that, among all ILC subsets, ILCPs elicited the strongest upregulation of adhesion molecules in ECs in vitro, mainly in a contact-dependent manner through the TNFR- and RANK-dependent engagement of the NF-κB pathway. Moreover, the ILCP-mediated activation of the ECs resulted to be functional by fostering the adhesion of other innate and adaptive immune cells. Interestingly, pre-exposure of ILCPs to human tumor cell lines strongly impaired this capacity. Hence, the ILCP-EC interaction might represent an attractive target to regulate the immune cell trafficking to tumor sites and, therefore, the establishment of an anti-tumor immune response.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Giulia Vanoni

    Department of Oncology, University of Lausanne - Ludwig Institute for Cancer Research, Epalinges, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3199-2412

  2. Giuseppe Ercolano

    Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  3. Simona Candiani

    Department of Earth Science, Environment and Life, University of Genova, Genova, Italy
    Competing interests
    The authors declare that no competing interests exist.

  4. Mariangela Rutigliani

    Department of Laboratory and Service, Histological and Anatomical Pathology, E.O. Galliera Hospital, Genova, Italy
    Competing interests
    The authors declare that no competing interests exist.

  5. Mariangela Lanata

    Department of Laboratory and Service, Histological and Anatomical Pathology,, E.O. Galliera Hospital, Genova, Italy
    Competing interests
    The authors declare that no competing interests exist.

  6. Laurent Derré

    Department of Urology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  7. Emanuela Marcenaro

    Department of Experimental Medicine and Centre of Excellence for Biomedical Research, University of Genova, Genova, Italy
    Competing interests
    The authors declare that no competing interests exist.

  8. Pascal Schneider

    Department of Biochemistry, University of Lausanne - Ludwig Institute for Cancer Research, Epalinges, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  9. Pedro Romero

    Department of Oncology, University of Lausanne, Epalinges, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  10. Camilla Jandus

    Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
    For correspondence
    camilla.jandus@unige.ch
    Competing interests
    The authors declare that no competing interests exist.

  11. Sara Trabanelli

    Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
    For correspondence
    sara.trabanelli@unige.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8648-1324

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PRIMA PR00P3_179727)

  • Camilla Jandus

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (FNS 31003A_156469)

  • Pedro Romero

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030A_176256)

  • Pascal Schneider

Compagnia di San Paolo (2019.866)

  • Emanuela Marcenaro

Compagnia di San Paolo (2019.866)

  • Simona Candiani

Associazione Italiana per la Ricerca sul Cancro (AIRC 5x1000-21147)

  • Emanuela Marcenaro

Associazione Italiana per la Ricerca sul Cancro (AIRC 5x1000-21147)

  • Simona Candiani

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Vincenzo Cerullo, University of Helsinki, Finland

Version history

  1. Received: May 12, 2020
  2. Accepted: February 5, 2021
  3. Accepted Manuscript published: February 8, 2021 (version 1)
  4. Version of Record published: February 18, 2021 (version 2)

Copyright

© 2021, Vanoni et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 873
    views
  • 127
    downloads
  • 6
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Giulia Vanoni
  2. Giuseppe Ercolano
  3. Simona Candiani
  4. Mariangela Rutigliani
  5. Mariangela Lanata
  6. Laurent Derré
  7. Emanuela Marcenaro
  8. Pascal Schneider
  9. Pedro Romero
  10. Camilla Jandus
  11. Sara Trabanelli
(2021)
Human primed ILCPs support endothelial activation through NF-κB signaling
eLife 10:e58838.
https://doi.org/10.7554/eLife.58838

Share this article

https://doi.org/10.7554/eLife.58838

Categories and tags

Research organism

Further reading

    1. Cancer Biology

    RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway

    Fang Huang, Zhenwei Dai ... Yang Wang
    Research Article

    Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. In addition, RBM7 negatively regulates the NF-κB cascade and an NF-κB inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer.

    1. Cancer Biology
    2. Immunology and Inflammation

    DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation

    Nicholas J Mullen, Surendra K Shukla ... Pankaj K Singh
    Research Article

    Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

    1. Cancer Biology
    2. Cell Biology

    CYRI-B-mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake

    Savvas Nikolaou, Amelie Juin ... Laura M Machesky
    Research Article Updated

    Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signalling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53-driven pancreatic cancer. Deletion of Cyrib (the gene encoding CYRI-B protein) accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a potential role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of the lysophosphatidic acid receptor 1. Overall, we implicate CYRI-B as a mediator of growth and signalling in pancreatic cancer, providing new insights into pathways controlling metastasis.