Alternative splicing of the inhibitory immune checkpoint receptor SLAMF6 generates a dominant positive form, boosting T-cell effector functions

Emma Hajaj, Elad Zisman, Shay Tzaban, Sharon Merims, Jonathan Cohen, Shiri Klein, Shoshana Frankenburg, Moshe Sade-Feldman, Yuval Tabach, Keren Yizhak, Ami Navon, Polina Stepensky, Nir Hacohen, Tamar Peretz, Andre Veillette, Rotem Karni, Galit Eisenberg, Michal Lotem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6D17–65 had a strong agonistic effect. The costimulatory action depended on protein phosphatase SHP1 and led to a cytotoxic molecular profile mediated by the expression of TBX21 and RUNX3. Patients treated with immune checkpoint blockade showed a shift toward SLAMF6D17–65 in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6D17–65 expression in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The yin-yang relationship of SLAMF6 splice isoforms may represent a balancing mechanism that could be exploited to improve cancer immunotherapy.

Original languageAmerican English
Pages (from-to)637-650
Number of pages14
JournalCancer Immunology Research
Volume9
Issue number6
DOIs
StatePublished - Jun 2021

Bibliographical note

Funding Information:
The work of E. Hajaj, E. Zisman, S. Tzaban, G. Eisenberg, S. Klein, S. Frankenburg, S. Merims, J. Cohen, and M. Lotem was supported by research grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Canadian Institutes of Health Research (CIHR), the Melanoma Research Alliance (MRA), the Israel Cancer Research Fund (ICRF), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF), The Azrieli Foundation, Deutsche Forschungsgemeinschaft (DFG), the Rosetrees Trust, and the Perlstein Family Fund. The authors wish to acknowledge the devoted technical work of Inna Ben-David, Anna Kuznetz, and Yael Gelfand. They thank Eli Pikarsky and Ofer Mandelboim for helpful discussions and Karen Pepper for editing the manuscript. They thank the G-INCPM, Weizmann Institute of Science, for data analysis. The authors are very grateful to Stewart and Maggie Greenberg for their long-standing support.

Funding Information:
E. Hajaj reports grants from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), Canadian Institutes of Health Research (CIHR), Melanoma Research Alliance (MRA), Israel Cancer Research Fund (ICRF), International Development Research Centre (IDRC), Israel Science Foundation (ISF), The Azrieli Foundation, Deutsche Forschungsgemeinschaft (DFG), Rose- trees Trust, and Perlstein Family Fund during the conduct of the study, as well as a patent for Nucleic Acid Agents Modulating SLAMF6 Isoforms pending. J. Cohen reports personal fees from Roche Pharmaceuticals, Novartis, MSD, Bristol-Myers Squibb, Medison Pharma, and Sanofi Aventis Israel Ltd. outside the submitted work. S. Frankenburg reports grants from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), Canadian Institutes of Health Research (CIHR), Melanoma Research Alliance (MRA), Israel Cancer Research Fund (ICRF), International Development Research Centre (IDRC), Israel Science Foundation (ISF), the Azrieli Foundation, Deutsche Forschungsgemeinschaft (DFG), Rosetrees Trust, and Perlstein Family Fund during the conduct of the study. N. Hacohen reports other support from BioNTech and Related Sciences outside the submitted work. T. Peretz reports grants from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), Canadian Institutes of Health Research (CIHR), Melanoma Research Alliance (MRA), Israel Cancer Research Fund (ICRF), International Development Research Centre (IDRC), Israel Science Foundation (ISF), The Azrieli Foundation, Deutsche Forschungsgemeinschaft (DFG), Rosetrees Trust, and Perlstein Family Fund during the conduct of the study. G. Eisenberg reports grants from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), Canadian Institutes of Health Research (CIHR), Melanoma Research Alliance (MRA), Israel Cancer Research Fund (ICRF), International Development Research Centre (IDRC), Israel Science Foundation (ISF), The Azrieli Foundation, Deutsche Forschungsgemeinschaft (DFG), Rose-trees Trust, and Perlstein Family Fund during the conduct of the study, as well as patent WO2020261265 pending. M. Lotem reports grants from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), Canadian Institutes of Health Research (CIHR), Melanoma Research Alliance (MRA), Israel Cancer Research Fund (ICRF), International Development Research Centre (IDRC), Israel Science Foundation (ISF), The Azrieli Foundation, Deutsche Forschungsge-meinschaft (DFG), Rosetrees Trust, and Perlstein Family Fund during the conduct of the study; grants from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), and personal fees from Oncohost and Merck outside the submitted work; and patent 160119 pending. No disclosures were reported by the other authors.

Publisher Copyright:
©2021 American Association for Cancer Research.

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