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 in vivo 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. Cancer Immunol Res; 6(2); 127-38. ©2018 AACR.
Highlights
One of the approaches used in the search for new immunomodulatory mechanisms is to identify lymphocyte surface receptors that are likely to have a regulatory function
To identify the specific binding sites of the soluble ectodomain on full-length SLAMF6, an overlapping peptide spot array was utilized. seSLAMF6 bound to sequences extending from proline at position 41 to leucine at position 127 (Supplementary Fig. S2)
We evaluated the effect of seSLAMF6 on activationinduced cell death (AICD), which is the result of vigorous activation of T cells [14]
Summary
One of the approaches used in the search for new immunomodulatory mechanisms is to identify lymphocyte surface receptors that are likely to have a regulatory function. The clinical success of targeting the immunoglobulin superfamily receptors PD-1 and CTLA-4 fueled interest in the uncharacterized members of several structural Ig-like subfamilies [1] One such family, the SLAM (signaling lymphocytic activation molecules) family of receptors, is typical of the homotypic-binding molecules involved in immunomodulation that are expressed on cells of hematopoietic origin. Our previous results [2] showed differential expression of SLAMF6 on T-cell clones with identical epitope specificity but different functional capacity. These data sparked our interest in this receptor in the context of antimelanoma CD8þ T-cell responses and prompted us to explore whether SLAMF6 is a function-determining receptor or a secondary chaperone.
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