Unveiling alternative splicing dynamics in activated T lymphocytes and their implications for immune checkpoint blockade efficacy
Elad Zisman,
Ori Stern,
Reyut Lewis,
Shay Tzaban,
Thomas Eisenhaure,
Sarah E. Henrickson,
Moshe Sade-Feldman,
Shira Silberman-Klein,
Galit Eisenberg,
Nir Hacohen,
Keren Yizhak,
Michal Lotem
Affiliations
Elad Zisman
The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel; Corresponding author
Ori Stern
The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel
Reyut Lewis
The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel
Shay Tzaban
The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel
Thomas Eisenhaure
Broad Institute of MIT and Harvard, Division of Allergy Immunology, Boston, MA, USA
Sarah E. Henrickson
Department of Pediatrics, the Children’s Hospital of Philadelphia, Philadelphia, and Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Moshe Sade-Feldman
Broad Institute of MIT and Harvard, Division of Allergy Immunology, Boston, MA, USA
Shira Silberman-Klein
The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel; Center for Melanoma and Cancer Immunotherapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Galit Eisenberg
The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel; Center for Melanoma and Cancer Immunotherapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; Hadassah Cancer Research Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Nir Hacohen
Broad Institute of MIT and Harvard, Division of Allergy Immunology, Boston, MA, USA
Keren Yizhak
Technion Israel Institute of Technology, Haifa, Israel
Michal Lotem
The Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine Hebrew University of Jerusalem, Jerusalem, Israel; Center for Melanoma and Cancer Immunotherapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; Hadassah Cancer Research Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel; Corresponding author
Summary: Alternative splicing (AS) generates diverse mRNA transcripts from a single gene, enhancing protein variety. This study examines AS during naive CD4 T cell activation, revealing that splicing events precede gene expression changes, evident as early as 6 h post-activation. Splicing alterations primarily impact pathways related to protein metabolism and mRNA processing, while gene expression dynamics affect immune regulatory genes. Notably, splicing isoforms favored soluble ectodomains of surface receptors, including CTLA4. CD8 T cells showed comparable patterns to CD4 cells, primarily differing in immune-related genes. Analysis of T cell–rich tumor samples from melanoma patients showed that AS events prevalent in the CD4 dataset correlated with positive responses to immune checkpoint inhibitors (ICIs). These findings suggest that activation-induced AS in T cells may play an immune regulatory role and be linked to ICI treatment outcomes.
