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Margot de Looff¹, Steven de Jong¹, Frank A E Kruyt¹

¹Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Frontiers in Immunology

|July 24, 2019

Abstract:

Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) signaling is far more complex than initially anticipated and can lead to either anti- or protumorigenic effects, hampering the successful clinical use of therapeutic TRAIL receptor agonists. Cell autonomous resistance mechanisms have been identified in addition to paracrine factors that can modulate apoptosis sensitivity. The tumor microenvironment (TME), consisting of cellular and non-cellular components, is a source for multiple signals that are able to modulate TRAIL signaling in tumor and stromal cells. Particularly immune effector cells, also part of the TME, employ the TRAIL/TRAIL-R system whereby cell surface expressed TRAIL can activate apoptosis via TRAIL receptors on tumor cells, which is part of tumor immune surveillance. In this review we aim to dissect the impact of the TME on signaling induced by endogenous and exogenous/therapeutic TRAIL, thereby distinguishing different components of the TME such as immune effector cells, neutrophils, macrophages, and non-hematopoietic stromal cells. In addition, also non-cellular biochemical and biophysical properties of the TME are considered including mechanical stress, acidity, hypoxia, and glucose deprivation. Available literature thus far indicates that tumor-TME interactions are complex and often bidirectional leading to tumor-enhancing or tumor-reducing effects in a tumor model- and tumor type-dependent fashion. Multiple signals originating from different components of the TME simultaneously affect TRAIL receptor signaling. We conclude that in order to unleash the full clinical potential of TRAIL receptor agonists it will be necessary to increase our understanding of the contribution of different TME components on outcome of therapeutic TRAIL receptor activation in order to identify the most critical mechanism responsible for resistance, allowing the design of effective combination treatments.

Insights

The tumor microenvironment (TME) significantly impacts tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) signaling, influencing treatment outcomes. Understanding these complex TME interactions is crucial for developing effective TRAIL-based cancer therapies.

Area of Science:

Oncology
Immunology
Cell Biology

Background:

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) signaling complexity hinders therapeutic TRAIL receptor agonist use.
Resistance mechanisms, including cell-autonomous and paracrine factors, modulate apoptosis sensitivity.
The tumor microenvironment (TME) provides signals influencing TRAIL signaling in tumor and stromal cells.

Purpose of the Study:

To dissect the TME's impact on endogenous and therapeutic TRAIL signaling.
To differentiate the roles of various TME components, including immune cells and stromal cells.
To consider non-cellular TME properties like mechanical stress, acidity, hypoxia, and glucose deprivation.

Main Methods:

Review of existing literature on TME components and their modulation of TRAIL signaling.
Analysis of interactions between immune effector cells (neutrophils, macrophages) and TRAIL/TRAIL-R system.
Evaluation of non-cellular TME factors (mechanical stress, pH, oxygen, nutrients) on TRAIL pathway.

Main Results:

TME interactions are complex and bidirectional, leading to tumor-enhancing or -reducing effects.
Multiple TME components simultaneously influence TRAIL receptor signaling outcomes.
Tumor-immune interactions, particularly involving TRAIL expressed on immune cells, play a role in tumor immune surveillance.

Conclusions:

Understanding TME contributions to TRAIL receptor signaling is vital for overcoming resistance.
Identifying critical resistance mechanisms within the TME is necessary for effective combination treatments.
Unleashing the clinical potential of TRAIL receptor agonists requires deeper insights into TME-mediated effects.

Read full analysis

Keywords:

TME TRAIL cancer cytokines immune suppression

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