Yigit and Wang et al. investigated the effects of SLAMF6, a homophilic receptor found on hematopoietic cells. Transfer of murine SLAMF6+ CLL cells into SLAMF6-/- recipients expanded PD-1+CD8+ T cells with impaired cytotoxicity, suggesting SLAMF6 counteracts T cell exhaustion. Treatment of WT mice with an agonist SLAMF6 Ab significantly decreased CLL tumor burden in the percutaneous space (where ADCC is ineffective), increased the number of antigen-experienced CD8+ T cells, and decreased B16 (SLAMF6-) tumor burden. Agonist SLAMF6 improved degranulation capacity of in vitro exhausted human CD8+ T cells.

Contributed by Katherine Turner

The tumor microenvironment in leukemia and solid tumors induces a shift of activated CD8+ cytotoxic T cells to an exhausted state, characterized by loss of proliferative capacity and impaired immunologic synapse formation. Efficient strategies and targets need to be identified to overcome T-cell exhaustion and further improve overall responses in the clinic. Here, we took advantage of the Emu-TCL1 chronic lymphocytic leukemia (CLL) and B16 melanoma mouse models to assess the role of the homophilic cell surface receptor SLAMF6 as an immune checkpoint regulator. The transfer of SLAMF6+ Emu-TCL1 cells into SLAMF6-/- recipients, in contrast to wild-type (WT) recipients, significantly induced expansion of a PD-1+ subpopulation among CD3+CD44+CD8+ T cells, which had impaired cytotoxic functions. Conversely, administering anti-SLAMF6 significantly reduced the leukemic burden in Emu-TCL1 recipient WT mice concomitantly with a loss of PD-1+CD3+CD44+CD8+ T cells with significantly increased effector functions. Anti-SLAMF6 significantly reduced leukemic burden in the peritoneal cavity, a niche where antibody-dependent cellular cytotoxicity (ADCC) is impaired, possibly through activation of CD8+ T cells. Targeting of SLAMF6 not only impacted tumor growth in B cell-related leukemia and lymphomas but also non-hematopoietic tumors like B16 melanoma, where SLAMF6 is not expressed. In vitro exhausted CD8+ T cells showed increased degranulation when anti-human SLAMF6 was added in culture. Taken together, anti-SLAMF6 both effectively corrected CD8+ T-cell dysfunction and had a direct effect on tumor progression. The outcomes of our studies suggest that targeting SLAMF6 is a potential therapeutic strategy.

Author Info: (1) Medicine, Division of Immunology, Beth Israel Deaconess Medical Center cterhors@bidmc.harvard.edu. (2) Medicine, Division of Immunology, Beth Israel Deaconess Medical Center. (

Author Info: (1) Medicine, Division of Immunology, Beth Israel Deaconess Medical Center cterhors@bidmc.harvard.edu. (2) Medicine, Division of Immunology, Beth Israel Deaconess Medical Center. (3) Department of Medical Oncology, Dana-Farber Cancer Institute. (4) Karches Center for Oncology Research, Feinstein Institute for Medical Research. (5) Department of Pathology, Massachusetts General Hospital. (6) Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center. (7) Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center. (8) (9) Feinstein Institute for Medical Research, Northwell Health. (10) Department of Medical Oncology, Dana-Farber Cancer Institute. (11) Department of Leukemia, University of Texas MD Anderson Cancer Center. (12) Pediatrics, Indiana University School of Medicine. (13) Biomedical Sciences, University of Barcelona. (14) Medicine, Division of Immunology, Beth Israel Deaconess Medical Center.