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
-
- 5,613
- views
-
- 753
- 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
Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.
-
- Cancer Biology
- Medicine
A doctoral-level internship program was developed at the University of North Carolina at Chapel Hill with the intent to create customizable experiential learning opportunities for biomedical trainees to support career exploration, preparation, and transition into their postgraduate professional roles. We report the outcomes of this program over a 5-year period. During that 5-year period, 123 internships took place at over 70 partner sites, representing at least 20 academic, for-profit, and non-profit career paths in the life sciences. A major goal of the program was to enhance trainees’ skill development and expertise in careers of interest. The benefits of the internship program for interns, host/employer, and supervisor/principal investigator were assessed using a mixed-methods approach, including surveys with closed- and open-ended responses as well as focus group interviews. Balancing stakeholder interests is key to creating a sustainable program with widespread support; hence, the level of support from internship hosts and faculty members were the key metrics analyzed throughout. We hypothesized that once a successful internship program was implemented, faculty culture might shift to be more accepting of internships; indeed, the data quantifying faculty attitudes support this. Furthermore, host motivation and performance expectations of interns were compared with results achieved, and this data revealed both expected and surprising benefits to hosts. Data suggests a myriad of benefits for each stakeholder group, and themes are cataloged and discussed. Program outcomes, evaluation data, policies, resources, and best practices developed through the implementation of this program are shared to provide resources that facilitate the creation of similar internship programs at other institutions. Program development was initially spurred by National Institutes of Health pilot funding, thereafter, successfully transitioning from a grant-supported model, to an institutionally supported funding model to achieve long-term programmatic sustainability.
