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

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.

Reviewing Editor

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

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.

Version 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.

Metrics

  • 5,290
    Page views
  • 730
    Downloads
  • 17
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Emma Hajaj
  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
(2020)
SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint
eLife 9:e52539.
https://doi.org/10.7554/eLife.52539

Share this article

https://doi.org/10.7554/eLife.52539

Further reading

    1. Cancer Biology
    2. Cell Biology
    Julian J A Hoving, Elizabeth Harford-Wright ... Alison C Lloyd
    Research Article

    Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during rat Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective Schwann cell migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased Schwann cell collective migration and increased clustering of Schwann cells within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.

    1. Cancer Biology
    2. Structural Biology and Molecular Biophysics
    Johannes Paladini, Annalena Maier ... Stephan Grzesiek
    Research Article

    Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2, and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force toward the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI-helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl’s activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.