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Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell

Fatma Aboulnasr1, Ashton Krogman1, Rondell P Graham2

  • 1Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 17, 2020
PubMed
Abstract

Insights

Tumor cells express TRAILshort, a variant that blocks cancer cell death. Blocking TRAILshort enhances tumor cell killing by immune cells, suggesting a new therapeutic target for cancer immunity.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from immune cells aids anti-tumor responses.
  • A TRAIL splice variant, TRAILshort, counteracts TRAIL-mediated cell death.
  • The expression and impact of TRAILshort in tumor cells remain largely unknown.

Purpose of the Study:

  • To investigate TRAILshort expression in human cancers.
  • To determine the functional impact of TRAILshort on tumor cell sensitivity to TRAIL and immune cell-mediated killing.
  • To explore TRAILshort as a potential therapeutic target in cancer immunity.

Main Methods:

  • Unbiased bioinformatics analysis to identify TRAILshort expression in primary human cancers.
  • Validation of expression using immunohistochemistry (IHC) and in situ hybridization (ISH).
  • Utilized TRAILshort-specific monoclonal antibodies (mAbs) to assess effects on cancer cell lines and primary tumor cells.

Main Results:

  • TRAILshort expression was detected in up to 40% of primary human tumors via RNA sequencing and IHC.
  • ISH confirmed TRAILshort expression is localized to tumor cells, not surrounding bystander cells.
  • TRAILshort inhibition increased cancer cell sensitivity to TRAIL-mediated killing in vitro and in xenograft models.
  • Immune effector cells from B-cell malignancy patients showed enhanced killing of autologous tumor cells when TRAILshort was blocked (P < 0.05).

Conclusions:

  • TRAILshort is present in primary human malignancies.
  • Blocking TRAILshort can enhance the efficacy of autologous immune effector cells against tumors.
  • TRAILshort blockade represents a potential strategy to improve anti-tumor immunity.

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