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RESEARCH HIGHLIGHT OPEN
Supporting tumor therapy by exercise: boosting T cell
immunity by myokines
Kristina Gebhardt1 and Karsten Krüger 1✉
Signal Transduction and Targeted Therapy     (      2022) 7:292 ; https://doi.org/10.1038/s41392-022-01116-6
In a recent study published in Cancer Cell, Kurz et al. reported how blood via increased adrenaline release. IL-15Ra cytotoxic T cells
exercise induces inhibitory effects on tumor growth by immuno- accumulate and infiltrate the tumor. This process is mediated by
logical processes.1 IL-15, but the study adds a central aspect of exercise immunology
The investigation of these mechanisms is particularly significant in the context of tumor diseases. The exact molecular signaling
because lifestyle factors are becoming increasingly important as pathways of IL-15 in CD8 cells need to be elucidated in future
adjunctive therapy for cancer. For many tumor diseases, such as studies. The model of pancreatic cancer used here has a special
colorectal cancer and breast cancer, there are convincing data that significance because it is a tumor disease with particularly high
physical activity has an impact on tumor growth, disease mortality. It seems important that a high infiltration with CD8+
progression, mortality, and recurrence rates. The mechanisms cells after exercise was also shown in human tumors, whereby the
are diverse and were initially attributed to indirect effects, such as human data support the results of the animal model. This does not
increased metabolic turnover, anti-inflammatory effects of activity, seem to happen in all tumor types through exercise.
regulatory functions on hormones, and antioxidative mechanisms. Another important aspect of the work is that physical activity
The study by Kurz et al. shows that exercise induces direct represents only an adjuvant therapy, which is intended to support
immunological effector functions via the release of myokines, primary therapy and reduce side effects. Thus, there is often a lack
which inhibits tumor growth.1 of scientific work that considers physical activity accompanying
The evidence that exercise has a direct impact on cellular pharmacological immunotherapies. Kurz et al. (2022) showed that
immunity to combat cancer is now convincing. The mobilizing and in the context of the use of a PD-1 checkpoint inhibitor physical
activating effects of each acute exercise bout on NK cells and activity has a therapy-supportive effect. At this point, it would still
T cells represent an essential process of the exercise-tumor be important to clarify the molecular mechanism by which type of
interactions. Here, adrenergic mechanisms interact with activating exercise the tumor tissue is sensitized to PD-1 immunotherapy
signals through myokines.2 In response to regular training and (Fig. 1).
increased cardiopulmonary fitness, long-term adaptations of the The findings give great importance to the myokine IL-15, which
hematopoietic system are observed, which are reflected by shifts is increased in circulation for 10–120min after both endurance
in proportions of T cell subpopulations towards more naive cells and strength training, regardless of age or training-status. Besides
and less highly differentiated cell types. In addition, acute exercise numerous metabolic effects, such as an improvement of glucose
and regular activity increase the proportion of regulatory T cells, uptake and fatty acid uptake into the skeletal muscle, IL-15 also
contributing to a balanced immunological environment. From seems to have numerous immunological functions, such as
animal experiments, we could learn that regular running affects activation of NK cells. The extent to which conclusions can be
the metabolism of CD8+ cells and that cytotoxic T cells develop drawn here about IL-15 as an exercise mimetic must be shown by
improved anti-tumor functions3. future studies. However, certainly physical activity can also make a
During any form of physical activity, the skeletal muscle significant contribution to tumor therapy via IL-15 release and the
contracts and releases various signaling molecules that act in an activation of CD8+ cells. If the holistic efficacy of exercise on tumor
autocrine, paracrine, and endocrine manner. The quality and diseases is considered, patients benefit from numerous other
quantity of the secreted molecules depend on the mode, duration, effects. For exercise therapy, it was convincingly shown that it
and intensity of the exercise. In addition to numerous metabolic reduces cancer-related fatigue, combats cachexia, increases
effects, myokines exhibit multiple immunological functions. Many muscular and cardiovascular performance, enhances quality of
of these molecules, such as IL-6, engage in intense crosstalk with life and many other significant factors for patients (Nadeau et al.,
T cells, involving mobilization as well as emigration and infiltration 2018).5
of organs and tissues. This has also been shown for the myokine From a clinical perspective, it will be important to investigate
IL-15. IL-15 is expressed in skeletal muscle and released into exercise recommendations more precisely. This includes the
circulation. Up to now, it is the only myokine promoting cytotoxic optimum modality, volume, duration, and intensity of exercise.
T cell survival.4 The exercise protocols in the study by Kurz et al. (2022) are
This is precisely where the study of Kurz et al. (2022) connects certainly a good start approaching differentiated exercise regimes
very well and fills a mechanistic gap. First, the study shows in the mouse model. However, all these models certainly have a
impressively that endurance training mobilizes T cells into the high barrier of transferability from murine models to the patient
1Department of Exercise Physiology and Sports Therapy, Justus-Liebig-University of Giessen, Giessen, Germany
Correspondence: Karsten Krüger (Karsten.krueger@sport.uni-giessen.de)
Received: 15 June 2022 Revised: 1 July 2022 Accepted: 6 July 2022
© The Author(s) 2022
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Supporting tumor therapy by exercise: boosting T cell immunity by myokines
Gebhardt and Krüger
2
Fig. 1 Systemic effects physical activity and associated local effects of exercise on the local tumor environment. Various modalities of exercise
cause the release of epinephrine, which has a mobilizing effect on T cells and NK cells via adrenergic receptors. Myokines then activate and
direct immune cells into the tumor, which can support therapy using checkpoint inhibitors (created by BioRender)
and training in clinical settings. For IL-15, systemic increases were 3. Rundqvist, H. et al. Cytotoxic T-cells mediate exercise-induced reductions in tumor
also induced by strength or resistance training accompanied by an growth. Elife 9, 59996 (2020).
anabolic effect on muscle tissue. This will raise the question to 4. Rosa-Neto, J. C. et al. Immunometabolism-fit: how exercise and training can
what extent strength training also has similar effects in tumor modify T cell and macrophage metabolism in health and disease. Exerc. Immunol.
therapy. Future studies should address the optimum exercise Rev. 28, 29–46 (2022).
program for a considerable IL-15 release in patients including 5. Nadeau, L. & Aguer, C. Interleukin-15 as a myokine: mechanistic insight into its
effect on skeletal muscle metabolism. Appl. Physiol. Nutr. Metab. 44, 229–238
other current therapeutic approaches in oncology. (2019).
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REFERENCES regulation or exceeds the permitted use, you will need to obtain permission directly
1. Kurz, E. et al. Exercise-induced engagement of the IL-15/IL-15Ralpha axis promotes from the copyright holder. To view a copy of this license, visit http://
anti-tumor immunity in pancreatic cancer. Cancer Cell, 40, 720–737 (2022). creativecommons.org/licenses/by/4.0/.
2. Pedersen, L. et al. Voluntary running suppresses tumor growth through epi-
nephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab.
23, 554–562 (2016). © The Author(s) 2022
Signal Transduction and Targeted Therapy       (    2022) 7:292