Genetic studies by Li et al. showed that SLAMF6 (also known as Ly108) functioned to repress T cell activation in mice and humans by triggering homotypic cis interactions at the T cell surface, suppressing TCR signaling through SHP-1 and limiting antitumor immunity, independent of SLAMF6 expression on tumor cells or APCs. SLAMF6 was expressed preferentially on Tpex cells, but not terminally exhausted Tex cells, and potent agonist mAbs that blocked T cell SLAMF6 cis binding boosted T cell activation and increased antitumor T cell responses, decreased numbers of Tex cells, and inhibited tumor growth in vivo, comparable to results obtained with SLAMF6 deficiency.
Contributed by Katherine Turner
ABSTRACT: Inhibitory receptors like PD-1 and CTLA-4 contribute to T cell dysfunction in cancer(1-3). Monoclonal antibodies (mAbs) blocking the interactions in trans of these receptors with their ligands on cancer cells or in the tumour microenvironment lead to clinical responses in some but not all types of cancer. Signalling lymphocytic activation molecule 6 (SLAMF6, also known as Ly108) is a homotypic receptor preferentially expressed on progenitor or stem-like exhausted T (T(pex)) cells, but not on terminally exhausted T (T(ex)) cells, as demonstrated in mouse models(4-9). In contrast to T(ex) cells, T(pex) cells retain the capacity for functional restoration after immune checkpoint blockade(10-12). The role of SLAMF6 in T cells remains ambiguous, as it has both activating and inhibitory effects, complicating its evaluation as a therapeutic target. Here we find that SLAMF6 was triggered in cis by homotypic interactions at the T cell surface. These interactions elicited inhibitory effects that suppressed activation of T cells and limited anti-tumour immunity, independently of SLAMF6 expression on tumour cells. mAbs against human SLAMF6 with a robust ability to disrupt the cis interactions strongly augmented T cell activation, reduced the proportions of exhausted T cells and inhibited tumour growth in vivo. Collectively, these findings show that SLAMF6 functions exclusively as a T cell inhibitory receptor, which is triggered by cis homotypic interactions. They also position SLAMF6 as a promising target for therapies aimed at enhancing anti-tumour immunity, regardless of SLAMF6 expression on tumour cells.
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. Department of Medicine, University of Montral, Montreal, Quebe
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. Department of Medicine, University of Montral, Montreal, Quebec, Canada. Department of Medicine, McGill University, Montreal, Quebec, Canada. (2) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. (3) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. Department of Medicine, McGill University, Montreal, Quebec, Canada. (4) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. Department of Medicine, McGill University, Montreal, Quebec, Canada. (5) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. (6) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China. (7) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. (8) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montreal, Quebec, Canada. andre.veillette@ircm.qc.ca. Department of Medicine, University of Montral, Montreal, Quebec, Canada. andre.veillette@ircm.qc.ca. Department of Medicine, McGill University, Montreal, Quebec, Canada. andre.veillette@ircm.qc.ca.
