Human cancers express TRAILshort, a dominant negative TRAIL splice variant, which impairs immune effector cell killing of tumor cells

Fatma Aboulnasr, Ashton Krogman, Rondell P. Graham, Nathan W. Cummins, Anisha Misra, Enrique Garcia-Rivera, Jeff R. Anderson, Sekar Natesampillai, Nicole Kogan, Murali Aravamudan, Zilin Nie, Thomas D.Y. Chung, Richard Buick, Andrew L. Feldman, Rebecca L. King, Anne J. Novak, Stephen M. Ansell, Saad Kenderian, Andrew David Badley

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Purpose: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to antitumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts antitumor immunity. Experimental Design: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with IHC and ISH. TRAILshort-specific mAbs were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. Results: As many as 40% of primary human tumors express TRAILshort by both RNA sequencing and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL-dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B-cell malignancies killed more autologous tumor cells in the presence compared with the absence of TRAILshort antibody (P < 0.05). Conclusions: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells.

Original languageEnglish (US)
Pages (from-to)5759-5771
Number of pages13
JournalClinical Cancer Research
Volume26
Issue number21
DOIs
StatePublished - Nov 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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