1. Cancer Biology
  2. Immunology and Inflammation
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SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint

  1. Emma Hajaj  Is a corresponding author
  2. Galit Eisenberg
  3. Shiri Klein
  4. Shoshana Frankenburg
  5. Sharon Merims
  6. Inna Ben David
  7. Thomas Eisenhaure
  8. Sarah E Henrickson
  9. Alexandra Chloé Villani
  10. Nir Hacohen
  11. Nathalie Abudi
  12. Rinat Abramovich
  13. Jonathan E Cohen
  14. Tamar Peretz
  15. Andre Veillette
  16. Michal Lotem
  1. Hadassah Hebrew University Hospital, Israel
  2. Broad Institute of MIT and Harvard, United States
  3. The Children's Hospital of Philadelphia, United States
  4. McGill University, Canada
Research Article
  • Cited 2
  • Views 2,981
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Cite this article as: eLife 2020;9:e52539 doi: 10.7554/eLife.52539

Abstract

SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 -/- mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 -/- CD8+ T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1 x SLAMF6 -/- cells, and upon activation, they acquired an effector-memory phenotype. Adoptive transfer of Pmel-1 x SLAMF6 -/- T cells to melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. LAG-3 expression was elevated in the SLAMF6 -/- cells, and the addition of the LAG-3-blocking antibody to the adoptive transfer protocol improved the SLAMF6 -/- T cells and expedited the anti-tumor response even further. The results from this study support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8+ T cells to eradicate tumors.

Data availability

Data have been deposited to dbGaP under the accession code phs000815.v2.p1. To access these data users may apply for access to the dbGaP data repository (https://www.ncbi.nlm.nih.gov/books/NBK482114/).

The following data sets were generated

Article and author information

Author details

  1. Emma Hajaj

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    For correspondence
    emma.hajaj@mail.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2437-3146
  2. Galit Eisenberg

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Shiri Klein

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Shoshana Frankenburg

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Sharon Merims

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Inna Ben David

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Thomas Eisenhaure

    Broad Institute of MIT and Harvard, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3999-3540
  8. Sarah E Henrickson

    Department of Pediatrics, Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alexandra Chloé Villani

    Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Nir Hacohen

    Broad Institute of MIT and Harvard, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Nathalie Abudi

    Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  12. Rinat Abramovich

    Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Jonathan E Cohen

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  14. Tamar Peretz

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  15. Andre Veillette

    McGill University, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  16. Michal Lotem

    Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.

Funding

Dr. Miriam and Shelodn G Adelson Medical Research Foundation

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

Fred Lovejoy Resident Research Fund Awards

  • Sarah E Henrickson

International Development Research Centre (108403)

  • Andre Veillette

Canadian Institutes of Health Research (FDN-143338)

  • Andre Veillette

Melanoma Research Alliance

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

Canadian Institutes of Health Research

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

International Development Research Centre

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

Israel Science Foundation

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

Azrieli Foundation

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

Deutsche Forschungsgemeinschaft

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

Rosetrees Trust

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

Perlstein family fund

  • Emma Hajaj
  • Galit Eisenberg
  • Shiri Klein
  • Shoshana Frankenburg
  • Sharon Merims
  • Inna Ben David
  • Jonathan E Cohen
  • Michal Lotem

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

Ethics

Animal experimentation: Animal studies were approved by the Institutional Review Board - Authority for biological and biomedical models, Hebrew University, Jerusalem, Israel (MD-14602-5 and MD-15421-5).

Human subjects: Human samples were collected according to the approved IRB: Partners 2006-P-002051 in the Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Reviewing Editor

  1. Yutaka Kawakami, Keio University School of Medicine, Japan

Publication history

  1. Received: October 7, 2019
  2. Accepted: February 11, 2020
  3. Accepted Manuscript published: March 3, 2020 (version 1)
  4. Version of Record published: March 16, 2020 (version 2)

Copyright

© 2020, Hajaj 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.

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