Effector function of CTLs is increased by irradiated colorectal tumor cells that modulate OX-40L and 4-1BBL and is reversed following dual blockade

BMC Res Notes. 2016 Feb 13:9:92. doi: 10.1186/s13104-016-1914-9.

Abstract

Background: Sub-lethal doses of ionizing radiation (IR) can alter the phenotype of target tissue by modulating genes that influence effector T cell activity. Previous studies indicate that cancer cells respond to radiation by up-regulating surface expression of death receptors, cell adhesion molecules and tumor-associated antigens (TAA). However, there is limited information available regarding how T cells themselves are altered following these interactions with irradiated tumor cells.

Methods: Here, several human colorectal tumor cell lines were exposed to radiation (0-10 Gy) in vitro and changes in the expression of molecules costimulatory to effector T cells (4-1BBL, OX-40L, CD70, ICOSL) were examined by flow cytometry. T cell effector function was assessed to determine if changes in these proteins were directly related to the changes in T cell function.

Results: We found OX-40L and 4-1BBL to be the most consistently upregulated proteins on the surface of colorectal tumor cells post-IR while ICOSL and CD70 remained largely unaltered. Expression of these gene products correlated with enhanced killing of irradiated human colorectal tumor cells by TAA-specific T-cells. Importantly, blocking of both OX-40L and 4-1BBL reversed radiation-enhanced T-cell killing of human tumor targets as well as T-cell survival and activation.

Conclusions: Overall, results of this study suggest that, beyond simply rendering tumor cells more sensitive to immune attack, radiation can be used to specifically modulate expression of genes that directly stimulate effector T cell activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand / metabolism*
  • CD27 Ligand / metabolism
  • Carcinoembryonic Antigen / metabolism
  • Cell Death / radiation effects
  • Cell Line, Tumor
  • Cell Survival / radiation effects
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Humans
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Lymphocyte Activation / immunology
  • Mucins / metabolism
  • OX40 Ligand / metabolism*
  • Radiation, Ionizing*
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / radiation effects

Substances

  • 4-1BB Ligand
  • CD27 Ligand
  • Carcinoembryonic Antigen
  • ICOSLG protein, human
  • Inducible T-Cell Co-Stimulator Ligand
  • Mucins
  • OX40 Ligand