SLAMF6​ deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint.

Emma Hajaj,Alexandra Chloé Villani,Nir Hacohen,Michal Lotem,Sarah E Henrickson,Shoshana Frankenburg,Inna Ben David,Andre Veillette,Rinat Abramovich,Tamar Peretz,Galit Eisenberg,Nathalie Abudi,Sharon Merims,Shiri Klein,Jonathan E Cohen,Thomas Eisenhaure

doi:10.7554/elife.52539

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 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.

Highlights

The SLAM family of receptors (SFRs) is a set of six receptors expressed on hematopoietic cells (Wu and Veillette, 2016; Cannons et al, 2011; Veillette, 2010; Calpe et al, 2008)
After 1 day of activation, there was an initial decrease in the SLAMF6 transcript that switched to over-expression (Figure 1C)
We initially evaluated the level of SLAM associated protein (SAP), the primary adaptor required for SLAMF6 signaling, encoded by the Sh2d1a gene, which was intact in the SLAMF6 -/- mice (Figure 6A)

Summary

Introduction

The SLAM family of receptors (SFRs) is a set of six receptors expressed on hematopoietic cells (Wu and Veillette, 2016; Cannons et al, 2011; Veillette, 2010; Calpe et al, 2008). All SFRs, except 2B4, are homotypic binders, that is they engage the same ectodomain sequence, either in cis (same cell) or in trans (adjacent cell) configuration. Most hematopoietic cell types express 3–5 members of the SLAM family

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Conclusion