Yigit, BurcuWang, Ninghaiten Hacken, ElisaChen, Shih-ShihBhan, Atul K.Suarez Fueyo, AbelKatsuyama, EriTsokos, George C.Chiorazzi, NicholasWu, Catherine J.Burger, Jan A.Herzog, Roland W.Engel, PabloTerhorst, Cox2020-10-092020-10-092019-09Yigit, B., Wang, N., Hacken, E. ten, Chen, S.-S., Bhan, A. K., Suarez-Fueyo, A., Katsuyama, E., Tsokos, G. C., Chiorazzi, N., Wu, C. J., Burger, J. A., Herzog, R. W., Engel, P., & Terhorst, C. (2019). SLAMF6 as a Regulator of Exhausted CD8+ T Cells in Cancer. Cancer Immunology Research. https://doi.org/10.1158/2326-6066.CIR-18-0664https://hdl.handle.net/1805/24037The 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 Eμ-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+ Eμ-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 Eμ-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 affected tumor growth not only in B cell–related leukemia and lymphomas but also in nonhematopoietic tumors such as 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.enPublisher PolicySLAMFCLLCTL exhaustionArticle