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

Abstract

BackgroundSub-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.MethodsHere, 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.ResultsWe 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.ConclusionsOverall, 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.

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

“…Research in our lab, and others, has shown that tumor cells exposed to doses within the hypofractionated range of radiation increase the expression of several cell surface proteins on tumor cells that are important for immune attack. Major histocompatibility (MHC) class I, death receptors (Fas/CD95 and TRAIL/CD253), and effector T cell costimulatory molecules (OX40L and 4-1BBL) exhibit increased expression on tumor cells surviving radiation [23][24][25][26]. Expression of these molecules subsequently promotes increased sensitivity to killing by CTLs [27,28].…”

Could OX40 agonist antibody promote activation of the anti‐tumor immune response in gastric cancer?

“…In cancer, increase the expression of OX40 by T lymphocytes in the colorectal tumor infiltrate after treatment with radiotherapy, promoting a better activation of the anti-tumor immune response. [19][20][21] In this study, we show that T cells in gastric cancer present important alterations in the expression of some costimulatory receptors that are essential for optimal function of T cells. As expect, there is a higher level of T cell activated in patients with gastric cancer.…”

“…Tregs recruit mast cells to different sites through secretion of IL‐9, while the OX40L (expressed on mast cell) and OX40 on T cell interaction inhibits the extent of the mast cell degranulation in asthma. In cancer, increase the expression of OX40 by T lymphocytes in the colorectal tumor infiltrate after treatment with radiotherapy, promoting a better activation of the anti‐tumor immune response …”

Systemic immune response associated with radiation therapy in B‑cell non‑Hodgkin's lymphoma of Waldeyer's ring

“…In order to explore how RT affects local or systemic immune system, irradiated lymphoma cells were investigated in the current study. The results demonstrated that 4-1BBL, CRT, HMGB1 and OX-40L were significantly overexpressed following irradiation of cells, and 4-1BBL and OX-40L are important co-stimulatory molecules in regulating T cell function (29,42). Activation of 4-1BBL and OX-40L increases T-cell generation and survival, and enhances T-cell killing of tumor cells (42).…”

“…The results demonstrated that 4-1BBL, CRT, HMGB1 and OX-40L were significantly overexpressed following irradiation of cells, and 4-1BBL and OX-40L are important co-stimulatory molecules in regulating T cell function (29,42). Activation of 4-1BBL and OX-40L increases T-cell generation and survival, and enhances T-cell killing of tumor cells (42). CRT and HMGB1 are important hallmarks of immunogenic cell death, which may promote the recruitment of dendritic cells (DCs) into the tumor, the uptake of dying tumor cells by DCs, and efficient antigen presentation to T cells (11).…”