SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint
- Hadassah Hebrew University Hospital, Israel
- Broad Institute of MIT and Harvard, United States
- The Children's Hospital of Philadelphia, United States
- 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/).
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.
Metrics
-
- 5,547
- views
-
- 750
- downloads
-
- 24
- 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)
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
Further reading
-
- Cancer Biology
- Evolutionary Biology
A central goal of cancer genomics is to identify, in each patient, all the cancer-driving mutations. Among them, point mutations are referred to as cancer-driving nucleotides (CDNs), which recur in cancers. The companion study shows that the probability of i recurrent hits in n patients would decrease exponentially with i; hence, any mutation with i ≥ 3 hits in The Cancer Genome Atlas (TCGA) database is a high-probability CDN. This study characterizes the 50–150 CDNs identifiable for each cancer type of TCGA (while anticipating 10 times more undiscovered ones) as follows: (i) CDNs tend to code for amino acids of divergent chemical properties. (ii) At the genic level, far more CDNs (more than fivefold) fall on noncanonical than canonical cancer-driving genes (CDGs). Most undiscovered CDNs are expected to be on unknown CDGs. (iii) CDNs tend to be more widely shared among cancer types than canonical CDGs, mainly because of the higher resolution at the nucleotide than the whole-gene level. (iv) Most important, among the 50–100 coding region mutations carried by a cancer patient, 5–8 CDNs are expected but only 0–2 CDNs have been identified at present. This low level of identification has hampered functional test and gene-targeted therapy. We show that, by expanding the sample size to 105, most CDNs can be identified. Full CDN identification will then facilitate the design of patient-specific targeting against multiple CDN-harboring genes.
-
- Cancer Biology
- Evolutionary Biology
Tumorigenesis, like most complex genetic traits, is driven by the joint actions of many mutations. At the nucleotide level, such mutations are cancer-driving nucleotides (CDNs). The full sets of CDNs are necessary, and perhaps even sufficient, for the understanding and treatment of each cancer patient. Currently, only a small fraction of CDNs is known as most mutations accrued in tumors are not drivers. We now develop the theory of CDNs on the basis that cancer evolution is massively repeated in millions of individuals. Hence, any advantageous mutation should recur frequently and, conversely, any mutation that does not is either a passenger or deleterious mutation. In the TCGA cancer database (sample size n=300–1000), point mutations may recur in i out of n patients. This study explores a wide range of mutation characteristics to determine the limit of recurrences (i*) driven solely by neutral evolution. Since no neutral mutation can reach i*=3, all mutations recurring at i≥3 are CDNs. The theory shows the feasibility of identifying almost all CDNs if n increases to 100,000 for each cancer type. At present, only <10% of CDNs have been identified. When the full sets of CDNs are identified, the evolutionary mechanism of tumorigenesis in each case can be known and, importantly, gene targeted therapy will be far more effective in treatment and robust against drug resistance.
