SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint
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/).
Article and author information
Author details
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.
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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