Abstract
PurposeInduction of IDO depends on the activation of AhR forming the AhR/IDO axis. Activated AhR can transcribe various target genes including cytotoxic and inhibiting receptors of NK cells. We investigated whether AhR and IDO levels as well as activating (NKG2D) and inhibiting (KIR2DL1) NK cell receptors are influenced by acute exercise and different chronic endurance exercise programs.Methods21 adult breast and prostate cancer patients of the TOP study (NCT02883699) were randomized to intervention programs of 12 weeks of (1) endurance standard training or (2) endurance polarized training after a cardiopulmonary exercise test (CPET). Serum was collected pre-CPET, immediately post-CPET, 1 h post-CPET and after 12 weeks post-intervention. Flow cytometry analysis was performed on autologous serum incubated NK-92 cells for: AhR, IDO, KIR2DL1 and NKG2D. Differences were investigated using analysis-of-variance for acute and analysis-of-covariance for chronic effects.ResultsAcute exercise: IDO levels changed over time with a significant increase from post-CPET to 1 h post-CPET (p = 0.03). KIR2DL1 levels significantly decreased over time (p < 0.01). NKG2D levels remained constant (p = 0.31). Chronic exercise: for both IDO and NKG2D a significant group × time interaction, a significant time effect and a significant difference after 12 weeks of intervention were observed (IDO: all p < 0.01, NKG2D: all p > 0.05).ConclusionBoth acute and chronic endurance training may regulate NK cell function via the AhR/IDO axis. This is clinically relevant, as exercise emerges to be a key player in immune regulation.
Highlights
A growing body of evidence suggests positive effects of physical exercise on cancer development, progress and mortality (Campbell et al 2019; Patel et al 2019; Meyerhardt et al 2006)
The decreased levels of Aryl hydrocarbon receptor (AhR) immediately after cardiopulmonary exercise test (CPET) might be of importance as recent findings have revealed induction of IDO depends on AhR expression (Nguyen et al 2014)
Despite NK cells’ ability to directly eliminate cancer cells, they are inhibited by several factors, one such factor being IDO mediated suppression (Wang et al 2012; Hornyak et al 2018)
Summary
A growing body of evidence suggests positive effects of physical exercise on cancer development, progress and mortality (Campbell et al 2019; Patel et al 2019; Meyerhardt et al 2006). NK cells cytotoxic ability is complex and is regulated by a range of activating and inhibitory receptors expressed on the NK cell surface (Jones et al 2012; Kumar 2018). In the context of cancer cell surveillance and removal, NKG2D binds to ligands of cellular stress often overexpressed on malignantly transformed cells triggering cytokine secretion or direct cellular cytotoxicity (Schmiedel and Mandelboim 2018). The killer cell immunoglobulin-like receptor (KIR) family is a dominant group of negative regulators which binds to self MHC- class I ligands (HLA-A, -B, -C) (Kumar 2018)
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