TY - JOUR
T1 - SLAMF6 as a regulator of exhausted CD8+ T cells in cancer
AU - Yigit, Burcu
AU - Wang, Ninghai
AU - Hacken, Elisa ten
AU - Chen, Shih Shih
AU - Bhan, Atul K.
AU - Suarez-Fueyo, Abel
AU - Katsuyama, Eri
AU - Tsokos, George C.
AU - Chiorazzi, Nicholas
AU - Wu, Catherine J.
AU - Burger, Jan A.
AU - Herzog, Roland W.
AU - Engel, Pablo
AU - Terhorst, Cox
N1 - Funding Information:
This work was supported by grants from the NIH PO1-AI065687 to C. Terhorst, N. Wang, and P. Engel. A. Suarez-Fueyo was supported by AI074549 (to G.C. Tsokos). E. ten Hacken is a Special Fellow of the Leukemia & Lymphoma Society.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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 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.
AB - 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 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.
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U2 - 10.1158/2326-6066.CIR-18-0664
DO - 10.1158/2326-6066.CIR-18-0664
M3 - Article
C2 - 31315913
AN - SCOPUS:85071787231
VL - 7
SP - 1485
EP - 1496
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 9
ER -