Soluble SLAMF6 Receptor Induces Strong CD8+ T-cell Effector Function and Improves Anti-Melanoma Activity In Vivo

Abstract

SLAMF6, a member of the SLAM (signaling lymphocyte activation molecules) family, is a homotypic-binding immune receptor expressed on NK, T, and B lymphocytes. Phosphorylation variance between T-cell subclones prompted us to explore its role in anti melanoma immunity. Using a 203-amino acid sequence of the human SLAMF6 (seSLAMF6) ectodomain, we found that seSLAMF6 reduced activation-induced cell death and had an antiapoptotic effect on tumor-infiltrating lymphocytes. CD8 T cells costimulated with seSLAMF6 secreted more IFNγ and displayed augmented cytolytic activity. The systemic administration of seSLAMF6 to mice sustained adoptively transferred transgenic CD8 T cells in comparable numbers to high doses of IL2. In a therapeutic model, lymphocytes activated by seSLAMF6 delayed tumor growth, and when further supported with seSLAMF6, induced complete tumor clearance. The ectodomain expedites the loss of phosphorylation on SLAMF6 that occurs in response to T-cell receptor triggering. Our findings suggest that seSLAMF6 is a costimulator that could be used in melanoma immunotherapy..

SLAMF6 clustering is required to augment T cell activation

“…SLAMF6 has been shown to have clinical significance [30–34]. In humans with X-linked lymphoproliferative (XLP) it has been demonstrated that blocking SLAMF4 and SLAMF6 via antibodies restores T cell function against B cell targets that also express SLAMF members [31].…”

“…In cancer, Eisenberg et al . has shown in great detail that administration of a soluble ectodomain of SLAMF6 increases the effector function CD8 + T cells against melanoma cells [34]. Furthermore, Yigit et al .…”

“…With an antibody based approach, drugs have the ability to dictate clustering via bi-specificity. This approach is not possible with soluble SLAMF6 ectodomain [34]. With these roles in human diseases in mind, it is imperative to further investigate the nature of SLAMF6 and how it behaves as an activating receptor in T cells.…”

Transcriptomic signature and metabolic programming of bovine classical and nonclassical monocytes indicate distinct functional specializations

“…Intermediate monocytes expressed the highest levels of adenosine deaminase ( ADA ), which is reported to act as a modulator of T-cell differentiation, increasing the generation of effector, memory and regulatory T cells (133). Both ncM and intM were enriched in transcripts for SLAMF6 , reported to boost IFN-γ production and cytolytic anti-tumor activity of human CD8 T cells in vitro (134). Furthermore, expression of ALCAM , encoding a ligand for CD6 on T cells, important for stabilizing the immunological synapse between APC and T cells (135) and reported to mediate extravasation of monocytes (136), was more than 3-fold higher expressed in ncM than in cM.…”

Alternative splicing of SLAMF6 in human T cells creates a co-stimulatory isoform that counteracts the inhibitory effect of the full-length receptor

“…Terhorst and our group have previously shown that canonical SLAMF6 serves as an inducer of T cell exhaustion and acts as an inhibitory checkpoint for T cells 13,22,23 . The results presented here with the fulllength SLAMF6 support this role.…”