SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/52539 |
| id |
doaj-e3efe8d8e0754d8bbbe2714fbaaca6ec |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Emma Hajaj Galit Eisenberg Shiri Klein Shoshana Frankenburg Sharon Merims Inna Ben David Thomas Eisenhaure Sarah E Henrickson Alexandra Chloé Villani Nir Hacohen Nathalie Abudi Rinat Abramovich Jonathan E Cohen Tamar Peretz Andre Veillette Michal Lotem |
| spellingShingle |
Emma Hajaj Galit Eisenberg Shiri Klein Shoshana Frankenburg Sharon Merims Inna Ben David Thomas Eisenhaure Sarah E Henrickson Alexandra Chloé Villani Nir Hacohen Nathalie Abudi Rinat Abramovich Jonathan E Cohen Tamar Peretz Andre Veillette Michal Lotem SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint eLife checkpoint immunotherapy cancer T cells |
| author_facet |
Emma Hajaj Galit Eisenberg Shiri Klein Shoshana Frankenburg Sharon Merims Inna Ben David Thomas Eisenhaure Sarah E Henrickson Alexandra Chloé Villani Nir Hacohen Nathalie Abudi Rinat Abramovich Jonathan E Cohen Tamar Peretz Andre Veillette Michal Lotem |
| author_sort |
Emma Hajaj |
| title |
SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint |
| title_short |
SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint |
| title_full |
SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint |
| title_fullStr |
SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint |
| title_full_unstemmed |
SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint |
| title_sort |
slamf6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel t cell checkpoint |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2020-03-01 |
| description |
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 antitumor 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. |
| topic |
checkpoint immunotherapy cancer T cells |
| url |
https://elifesciences.org/articles/52539 |
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doaj-e3efe8d8e0754d8bbbe2714fbaaca6ec2021-05-05T20:52:50ZengeLife Sciences Publications LtdeLife2050-084X2020-03-01910.7554/eLife.52539SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpointEmma Hajaj0https://orcid.org/0000-0003-2437-3146Galit Eisenberg1Shiri Klein2Shoshana Frankenburg3Sharon Merims4Inna Ben David5Thomas Eisenhaure6https://orcid.org/0000-0003-3999-3540Sarah E Henrickson7Alexandra Chloé Villani8Nir Hacohen9Nathalie Abudi10Rinat Abramovich11Jonathan E Cohen12Tamar Peretz13Andre Veillette14Michal Lotem15Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, Israel; Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hebrew University, Jerusalem, IsraelSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, IsraelSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, IsraelSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, IsraelSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, IsraelSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, IsraelBroad Institute of MIT and Harvard, Cambridge, United StatesBroad Institute of MIT and Harvard, Cambridge, United States; Boston Children's Hospital, Department of Pediatrics, Boston, United StatesBroad Institute of MIT and Harvard, Cambridge, United States; Center for Cancer Research, Massachusetts General Hospital, Charlestown, United States; Department of Medicine, Harvard Medical School, Boston, United States; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, United StatesBroad Institute of MIT and Harvard, Cambridge, United States; Center for Cancer Research, Massachusetts General Hospital, Charlestown, United States; Department of Medicine, Harvard Medical School, Boston, United StatesWohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, Israel; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, IsraelWohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, Israel; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, IsraelSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, IsraelSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, IsraelIRCM, Montreal Clinical Research Institute, Montreal, CanadaSharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel; Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem, Israel; Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hebrew University, Jerusalem, IsraelSLAMF6 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 antitumor 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.https://elifesciences.org/articles/52539checkpointimmunotherapycancerT cells |