SLAMF6 as a regulator of exhausted CD8+ T cells in cancer

Burcu Yigit, Ninghai Wang, Elisa ten Hacken, Shih Shih Chen, Atul K. Bhan, Abel Suarez-Fueyo, Eri Katsuyama, George C. Tsokos, Nicholas Chiorazzi, Catherine J. Wu, Jan A. Burger, Roland W. Herzog, Pablo Engel, Cox Terhorst

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1485-1496
Number of pages12
JournalCancer immunology research
Volume7
Issue number9
DOIs
Publication statusPublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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