Professional Documents
Culture Documents
https://doi.org/10.1007/s00432-017-2573-5
Abstract
Purpose Physical activity can impact the immune system in different ways, e.g. by alteration of the humoral and cellular
immune response. Physical activity at medium intensity enhances numbers of cytotoxic T cells, NK cells and macrophages
in healthy people. The aim of this study was to compare the effects of endurance and resistance training on the immune
system in breast cancer patients during adjuvant chemotherapy.
Methods In a prospective, controlled and randomized intervention exploratory trial, 12-week supervised endurance or resist-
ance training were compared with usual care twice a week. Endpoints were the absolute numbers of the immune cells such
as CD3+ T lymphocytes including CD4+- and CD8+, αβ T cells, γδT cells, CD3−/CD16+/56+ NK cells and CD19+ B cells,
before and after 12 weeks of treatment. Cell numbers were analyzed using fluorescence-activated cell sorting.
Results Despite different physical interventions in all groups immune cell count decreased in CD3 T cells including TCR αβ
and CD4 T cells, NK cells and CD19 B cells 12 weeks after initiation of chemotherapy and start of the physical intervention
program, while the reduction of γδ T cells and CD8 T cells is less prominent in the RT and UC group.
Conclusion Chemotherapy led to a decrease in nearly all measured immune cells. In this study, physical intervention with
endurance or resistance training did not suppress cellular immunity any further. Larger multicenter trials are needed to evalu-
ate the exact impact of sports intervention on immune cell subpopulations.
13
Vol.:(0123456789)
Journal of Cancer Research and Clinical Oncology
healthy athletes and older adults has already been studied • Screening
well for many years (Brolinson and Elliott 2007; Gleeson • Determination of the immune parameter
T1 Baseline • Randomization
and Walsh 2012; Pedersen 1991; Pedersen and Bruunsgaard
1995; Phillips et al. 2010), the impact on the immune system • Arm 1: Resistance training
• Arm 2: Endurance training
of cancer patients and on disease progression has not been Chemotherapy • Arm 3: Usual care
adequately investigated. Initial findings on the immunologi-
cal impact of physical activity in cancer patients have been • Determination of the immune parameter
made in the 1990s. (Nieman et al. 1995; Peters et al. 1994; T2 End of study
In this prospective, controlled and randomized intervention The analyses included data of patients who attended a mini-
exploratory trial 12-week supervised resistance training mum of 70% of the training sessions according to the proto-
(RT) or endurance training (ET) were compared with usual col. Immunological profiles were assessed at baseline on the
care (UC) in women with primary moderate or high risk day when chemotherapy (T1) was initiated, 12 week after
breast cancer during adjuvant chemotherapy. An overview initiation of chemotherapy and physical intervention (T2).
of the study flow is shown in Fig. 1. Patients were recruited Primary endpoints of this trial were the absolute number
at an academical breast unit in Germany. Inclusion criteria count of T cell receptor (TCR) αβ and TCR γδ CD3+ T cells
were: primary moderate or high risk breast cancer, planned (CD3+), CD3+ TCR γδ T cells alone (γδ T cells), CD3+
adjuvant or neoadjuvant chemotherapy with epirubicine/ TCR αβ T cells (αβ T cells), αβ T helper cells (CD4+), αβ-
cyclophosphamide (EC) (4×, q3w) followed by paclitaxel and γδ cytotoxic T cells (CD8+), CD8− γδ T cells, NK cells
(12×, q1w), fluorouracil/epirubicine/cyclophosphamide (CD3−/CD16+/56+) and B cells (CD19). Obtained results
(3×, q3w) followed by doxetaxel (3×, q3w) or further at baseline were compared across the treatment and control
chemotherapy regimen 18–70 years old women and fitness groups using an independent t test for continuous outcomes.
to exercise. Exclusion criteria comprised, acute infectious Statistical significance for the t test at T1 and T2 was set at
disease, severe cardiac disease (New York Heart Associa- the probability level of p < 0.05. The effects are expressed
tion functional class III; myocardial infarction < 3 months), with mean and standard deviations. The analyses were per-
severe pulmonary or renal insufficiency (glomerular filtra- formed using the SPSS system for windows (Version: PASW
tion rate < 30%), serious neurological disorders, less than 18).
13
Journal of Cancer Research and Clinical Oncology
Table 1 Anamnestic and n Age (years) Height (cm) T1 weight (kg) T2 weight (kg) p value
anthropometric parameters of (mean ± d) (mean ± d) (mean ± d) (mean ± d)
the patients
RT 21 53 ± 12.55 176 ± 5.63 74.8 ± 15.83 75.7 ± 10.28 0.82 (n.s.)
ET 20 56 ± 10.15 175 ± 4.87 72.1 ± 12.35 73.2 ± 9.10 0.75 (n.s.)
UC 26 54 ± 11.19 177 ± 2.57 76.3 ± 15.40 76.1 ± 13.50 0.96 (n.s.)
Table 2 Different Chemotherapies of the intervention groups and the standard care group
4 × epirubicin/cyclo- 4 × epirubicin/cyclo- 3 × fluorouracil/Epiru- 3 × fluorouracil/ Further chemo- Further chemo-
phosphamid, q3w, phosphamid, q3w fol- bicin cyclophospha- epirubicin cyclophos- therapy-regimen therapy-regi-
followed by 12 × taxol lowed by 4 × docetaxel, mid, q3w, followed by phamid, q3w, followed men + herceptin
weekly q3w 3 × docetaxel, q3w by 3 × docetaxel,
q3w + herceptin
RT 10 3 1 1 5 1
ET 16 2 0 2 0
UC 13 6 1 5 1
13
Journal of Cancer Research and Clinical Oncology
lymphocytes including CD4+ and CD8+ T cell subsets as Previous studies that investigated the influence of physi-
well as NK cells and B lymphocytes (Hensley et al. 2012; cal activity on the immune system of breast cancer patients
Nicholson et al. 1997). Since γδ T cells are not detected by focused mainly on the time after medical treatment and
M6T, we adapted γδ T cell staining and monitoring from the described the effect on the cells of the immune system and
BD Trucount™ Tube technical data sheet (version 8/2010) changes in cytotoxins. In a systematic review (Schmidt et al.
as described elsewhere (Oberg et al. 2014). The blood sam- 2017a, b) we identify ten studies, who investigate especially
ple was taken before the first chemotherapy (T1) and after in the effects of physical training on the immune system
12 weeks before the fourth chemotherapy. (NK cells, monocytes macrophages, lymphocytes or the
tumor-associated macrophages, interleukines and the tumor
necrosis factor (TNF)) of breast cancer patients (Evans et al.
Results 2015; Fairey et al. 2005; Hagstrom et al. 2016; Hutnick et al.
2005; Mohamady et al. 2013; Nieman et al. 1995; Peters
As shown in Table 3, the absolute number of CD3+ T lym- et al. 1995, 1994; Saxton et al. 2014; Zimmer et al. 2016).
phocytes drastically decreased in all groups within 12 weeks The results of these studies show that the NK cell popula-
after the initiation of chemotherapy and physical interven- tions increase or their function improves due to different
tion (RT: − 19.32%, p: 046; ET: − 25.78%, p: 0.001; UC: sports interventions. Fairey et al. and Peters et al. report in
− 21.54%, p: 0.001). While the decrease of absolute CD3 T addition a change in the lymphocyte population. Both the
cell number was highly significant in the ET and UC group, NK-cells and also the lymphocytes play an important role
a non-significant reduction was observed in the RT group. in the immune system and the immunoreaction (Fairey et al.
Regarding the different C D3+ T cell subsets, αβ T cells 2005; Peters et al. 1995, 1994).
highly significantly decreased in all groups with less extent Our study represents a first attempt to obtain informa-
in the RT group (RT: − 19.84%; p: 0.04; ET: − 26.22%; p: tion about the influence of several training programs on
< 0.0001; UC: − 21.86% p: < 0.0001), whereas the absolute the immune system of breast cancer patients undergoing
γδ T cell number was nearly stable, in contrast to αβ T cells chemotherapy. In contrast to our results, Hagstrom et al.
within 12 weeks (RT: +0.89%, p: 0.95; ET: 16.16%, p: 0.14; could determine a positive effect of physical training on
UC: − 14.93%, p: 0.12). In detail, γδ T cells were stable the immune system of breast cancer patients in aftercare.
within 12 weeks in the RT and only slightly decreased in 39 BC patients were randomized to an intervention and a
the ET- and UC group. Interestingly, similar results as for control group. The 20 participants in the intervention group
γδT cell population were measured for C D8+ T cells which completed equipment training over 16 weeks at 80% of the
co-express either the TCR αβ or occasionally TCR γδ(RT: “one repetition maximum”. The NK-cells, the “natural killer
− 10.93% p: 0.13; ET: − 16.89% p: 0.04; UC: − 4.00% p: T-cells” (NKT) and the inflammation markers TNF-α, IL-6,
0.41) whereas a significant decrease of the CD4+ T cells IL-10 and CRP (C reactive protein) were measured before
was detected in all three groups (RT: − 31.96% p: 0.001; ET: and after the intervention. The results showed an altered
− 35.14%; p: 0.001; UC: − 29.17% p: 0.001). TNF-α expression in NK- and NKT cells of the intervention
In addition, NK cells (CD16/CD56) were slightly reduced group compared to the control group (Hagstrom et al. 2016).
in the RT and UC group and highly significant in the ET This result corresponds to findings obtained in other stud-
group (RT: − 22.88% p: 0.53; ET: − 40.16% p: 0.001; UC: ies (Fairey et al. 2002; Hagstrom et al. 2016; Hutnick et al.
− 19.39% p: 0.05). Extremely striking was the highly signifi- 2005; Mohamady et al. 2013; Saxton et al. 2014; Zimmer
cant reduction of the B cells (CD19) in all three groups (RT: et al. 2016).
− 86.60%; p: 0.001; ET: − 92.59%, p: 0.001; UC: − 88.76%, In our study the absolute cell number of NK cells, B cells
p: 0.001). The differences of all immune parameters between and T cells decreased in the intervention groups as well in
the arms are not significant. the control group with a lowest reduction of the CD3 T cells
to T2 in the resistance group. While in the past, discouraged
from physical activity during chemotherapy on the basis of
Discussion a physical activity induced immunosuppression, our data
describe that supervised physical activities has no influence
Meanwhile there is evidence for a benefit of physical activity on chemotherapy induced immunosuppression. Slightly no
during medical treatment and in aftercare of breast cancer significant higher values or lower reduction of the subsets
patients. Previous studies documented an improvement in of immune parameter (γδ T cells and CD8 T cells) from T1
physical function, fatigue and quality of life after interven- to T2 we observed in the resistance group.
tional physical activity (Adamsen et al. 2009; Baumann et al. The different results of the studies can be attributed to the
2013; Courneya et al. 2014a, b; Mishra et al. 2012; Schmidt various study designs. While the present study concentrates
et al. 2015). on the phase during chemotherapy, previous studies focused
13
Table 3 Immune cells at T1, T2, T3 in the RT, EC an UC-group
CD3 CD4 CD8 CD19
T1 vs. T2 p % Change T1 vs. T2 p % Change T1 vs. % Change T1 vs. T2 p % Change
value T1/T2 value T1/T2 T2 p T1/T2 value T1/T2
value
RT
T1 1252.82 ± 422.86 0.46 − 19.32 827.33 ± 317.86 0.001 − 31.96 359.67 ± 156.92 0.13 − 10.93 191.81 ± 78.78 0.001 − 86.60
T2 1010.81 ± 484.96 562.86 ± 210.31 320.33 ± 208.24 25.71 ± 33.09
ET
T1 1153.40 ± 365.05 0.001 − 25.78 753.60 ± 259.90 0.001 − 35.14 339.40 ± 173.98 0.04 − 16.89 172.70 ± 71.93 0.001 − 92.59
T2 856.00 ± 379.00 488.75 ± 192.85 282.05 ± 152.28 12.80 ± 11.07
UC
Journal of Cancer Research and Clinical Oncology
T1 1255.48 ± 340.32 0.001 − 21.54 788.60 ± 199.43 0.001 − 29.17 369.84 ± 150.37 0.41 − 4.00 183.20 ± 79.71 0.001 − 88.76
T2 985.00 ± 323.98 558.60 ± 159.44 355.00 ± 170.71 20.6 ± 20.08
T2 0.41 0.36 0.40 0.21
between
the
groups
p-value
T2 Δ 0.91 0.8 0.41 0.97
between
the
groups
p-value
CD16/56 γδ αβ
T1 vs. T2 p value % Change T1/T2 T1 vs. T2 p % Change T1/T2 T1 vs. T2 p % Change T1/T2
value value
RT
T1 230.14 ± 118.26 0.53 − 22.88 42.67 ± 25.96 0.95 + 0.89 1209.76 ± 411.78 0.04 − 19.84
T2 177.48 ± 118.05 43.05 ± 29.74 969.38 ± 473.59
ET
T1 182.65 ± 82.44 0.001 − 40.16 41.75 ± 47.66 0.14 − 16.16 1112.35 ± 355.27 0.00 − 26.22
T2 109.30 ± 42.30 35.00 ± 52.45 820.70 ± 358.57
UC
T1 188.76 ± 79.30 0.05 − 19.39 53.84 ± 66.48 0.12 − 14.93 1203.64 ± 328.85 0.00 − 21.86
T2 152.16 ± 99.20 45.80 ± 48.65 940.48 ± 308.83
T2 between 0.07 0.72 0.42
the groups
p-value
13
Journal of Cancer Research and Clinical Oncology
% Change T1/T2
therapy. Furthermore, the sport and exercise programs in the
studies cited differ in several points, so that comparability
is limited. The intervention programs differ with respect to
their intensity, duration of the individual training sessions,
their frequency and the overall extent of physical activity.
T1 vs. T2 p
activity.
γδ
Conclusion
CD16/56
0.43
Table 3 (continued)
13
Journal of Cancer Research and Clinical Oncology
a breast cancer diagnosis such as the dose/effect relation- Fulwyler MJ (1965) Electronic separation of biological cells by vol-
ship are possible only after further prospective, standardized ume. Science 3698:910–911
Gießing J (2003) Trainingsplanung und Steuerung beim Muskelauf-
and controlled clinical studies confirming the assumption of bautraining. Leistungssport 4:26–31
an immunomodulating effect of physical activity. Further Gleeson M, Walsh NP (2012) The BASES expert statement on exer-
studies should be the focus of these points to enable more cise, immunity, and infection. J Sports Sci 3:321–324
precise statements on the intensity, duration and extent of Hagstrom AD, Marshall PWM, Lonsdale C, Papalia S, Cheema BS,
Toben C, Baune BT, Fiatarone Singh MA, Green S (2016) The
sport activities. effect of resistance training on markers of immune function and
inflammation in previously sedentary women recovering from
Acknowledgements With kind support of the Cancer Society breast cancer: a randomized controlled trial. Breast Cancer Res
Schleswig–Holstein, the Krumme Foundation and of the Foundation Treat 3:471–482
Living with Cancer (Stiftung Leben mit Krebs), O. Stremme, MD, our Hayes SC, Rye S, Disipio T, Yates P, Bashford J, Pyke C, Saunders
medical technicians S. Haman and F. Rösel, our study nurse B. Schütt C, Battistutta D, Eakin E (2013) Exercise for health: a rand-
and K.Yoo-Ott as well as S. Ussat for technical assistance. omized, controlled trial evaluating the impact of a pragmatic,
translational exercise intervention on the quality of life, func-
Compliance with ethical standards tion and treatment-related side effects following breast cancer.
Breast Cancer Res Treat 1:175–186
Hensley TR, Easter AB, Gerdts SE, Rosa SC de, Heit A, McElrath
Conflict of interest There are no conflicts of interest. MJ, Andersen-Nissen E (2012) Enumeration of major peripheral
blood leukocyte populations for multicenter clinical trials using
a whole blood phenotyping assay. J Vis Exp 67:e4302
Hutnick NA, Williams NI, Kraemer WJ, Orsega-Smith E, Dixon
RH, Bleznak AD, Mastro AM (2005) Exercise and lymphocyte
References activation following chemotherapy for breast cancer. Med Sci
Sports Exerc 11:1827–1835
Adamsen L, Quist M, Andersen C, Moller T, Herrstedt J, Kronborg Markes M, Brockow T, Resch KL (2006) Exercise for women receiv-
D, Baadsgaard MT, Vistisen K, Midtgaard J, Christiansen B, ing adjuvant therapy for breast cancer. Cochrane Database Syst
Stage M, Kronborg MT, Rorth M (2009) Effect of a multimodal Rev 4:CD005001
high intensity exercise intervention in cancer patients undergo- McTiernan A (2008) Mechanisms linking physical activity with can-
ing chemotherapy: randomised controlled trial. BMJ 339:b3410 cer. Nat Rev Cancer 3:205–211
Baumann FT, Bloch W, Weissen A, Brockhaus M, Beulertz J, Zim- Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein BR,
mer P, Streckmann F, Zopf EM (2013) Physical activity in breast Topaloglu O (2012) Exercise interventions on health-related
cancer patients during medical treatment and in the aftercare—a quality of life for people with cancer during active treatment.
review. Breast care 5:330–334 Clin Otolaryngol 5:390–392
Borg G (1998) Borg’s perceived exertion and pain scales. Human Mohamady TM, Borhan WH, Abdallah W, AbdelGhani S (2013)
Kinetics Borg’s perceived exertion and pain scales, Champaign Effect of selected exercise program on natural killer cytotoxic
Brolinson PG, Elliott D (2007) Exercise and the immune system. Clin cells activity of post-mastectomy patients. Beni Suef Univ J
Sports Med 3:311–319 Basic Appl Sci 2:114–119
Brzycki M (1993) Strength testing—predicting a one-rep max from Nicholson JK, Stein D, Mui T, Mack R, Hubbard M, Denny T (1997)
reps-to-fatigue. J Phys Educ Recreat Dance 1:88–90 Evaluation of a method for counting absolute numbers of cells
Courneya KS, McKenzie DC, Mackey JR, Gelmon K, Friedenreich with a flow cytometer. Clin Diagn Lab Immunol 3:309–313
CM, Yasui Y, Reid RD, Cook D, Jespersen D, Proulx C, Dolan Nieman DC, Cook VD, Henson DA, Suttles J, Rejeski WJ, Ribisl
LB, Forbes CC, Wooding E, Trinh L. Segal RJ (2013) Effects of PM, Fagoaga OR, Nehlsen-Cannarella SL (1995) Moderate
exercise dose and type during breast cancer chemotherapy: multi- exercise training and natural killer cell cytotoxic activity in
center randomized trial. J Natl Cancer Inst 23:1821–1832 breast cancer patients. Int J Sports Med 5:334–337
Courneya KS, McKenzie DC, Mackey JR, Gelmon K, Friedenreich Oberg HH, Kellner C, Peipp M, Sebens S, Adam-Klages S,
CM, Yasui Y, Reid RD, Vallerand JR, Adams SC, Proulx C, Gramatzki M, Kabelitz D, Wesch D (2014) Monitoring circu-
Dolan LB, Wooding E, Segal RJ (2014a) Subgroup effects in a lating γδ T cells in cancer patients to optimize γδ T cell-based
randomised trial of different types and doses of exercise during immunotherapy. Front Immunol 5:643
breast cancer chemotherapy. B J Cancer 9:1718–1725 Pawelec G, Hirokawa K, Fülöp T (2001) Altered T cell signalling in
Courneya KS, Segal RJ, McKenzie DC, Dong H, Gelmon K, Frieden- ageing. Mech Ageing Dev 14:1613–1637
reich CM, Yasui Y, Reid RD, Crawford JJ, Mackey JR (2014b) Pedersen BK (1991) Influence of physical activity on the cellu-
Effects of exercise during adjuvant chemotherapy on breast cancer lar immune system: mechanisms of action. Int J Sports Med
outcomes. Med Sci Sports Exerc 9:1744–1751 12:23–29
Evans ES, Hackney AC, McMurray RG, Randell SH, Muss HB, Deal Pedersen BK, Bruunsgaard H (1995) How physical exercise influences
AM, Battaglini CL (2015) Impact of acute intermittent exercise the establishment of infections. Sports Med 6:393–400
on natural killer cells in breast cancer survivors. Integr Cancer Peters C, Lötzerich H, Niemeier B, Schüle K, Uhlenbruck G (1994)
Ther 5:436–445 Influence of a moderate exercise training on natural killer cyto-
Fairey AS, Courneya KS, Field CJ, Mackey JR (2002) Physical exercise toxicity and personality traits in cancer patients. Anticancer Res
and immune system function in cancer survivors: a comprehensive 14:1033–1036
review and future directions. Cancer 2:539–551 Peters C, Lotzerich H, Niemeir B, Schule K, Uhlenbruck G (1995)
Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Martin BS, Exercise, cancer and the immune response of monocytes. Anti-
Mackey JR (2005) Effect of exercise training on C-reactive protein cancer Res 1:175–179
in postmenopausal breast cancer survivors: a randomized con- Phillips MD, Flynn MG, McFarlin BK, Stewart LK, Timmerman KL
trolled trial. Brain Behavior Immun 5:381–388 (2010) Resistance training at eight-repetition maximum reduces
13
Journal of Cancer Research and Clinical Oncology
the inflammatory milieu in elderly women. Med Sci Sports Exerc SchneiderCM, Gruenigen VE von, Schwartz AL. American Col-
2:314–325 lege of Sports Medicine roundtable on exercise guidelines for
Saxton JM, Scott EJ, Daley AJ, Woodroofe M, Mutrie N, Crank cancer survivors. Med Sci Sports Exerc 7:1409–1426
H, Powers HJ, Coleman RE (2014) Effects of an exercise and Senchina DS, Kohut ML (2007) Immunological outcomes of exercise
hypocaloric healthy eating intervention on indices of psychologi- in older adults. Clin Interv Aging 1:3–16
cal health status, hypothalamic-pituitary-adrenal axis regulation Uhlenbruck G, Order U (1991) Can endurance sports stimulate immune
and immune function after early-stage breast cancer: a randomised mechanisms against cancer and metastasis? Int J Sports Med
controlled trial. Breast cancer res 16:R39 1:63–68
Schmidt T, Weisser B, Dürkop J, Jonat W, van Mackelenbergh M, Wahlund H (1948) Determination of the physical working capacity.
Röcken C, Mundhenke C (2015) Comparing endurance and resist- Acta Med Scand Suppl 132:215
ance training with standard care during chemotherapy for patients Zimmer P, Baumann FT, Bloch W, Zopf EM, Schulz S, Latsch J, Schol-
with primary breast cancer. Anticancer Res 10:5623–5629 lmayer F, Shimabukuro-Vornhagen A, Bergwelt-Baildon M von,
Schmidt T, Hermes A, Weisser B (2017a) Physical training influences Schenk A (2016) Impact of a half marathon on cellular immune
the immune system of breast cancer patients. Dtsch Z Sportmed system, pro-inflammatory cytokine levels, and recovery behavior
03:53–60 of breast cancer patients in the aftercare compared to healthy con-
Schmidt T, van Mackelenbergh M, Wesch D, Mundhenke (2017b) trols. Eur J Haematol 2:152–159. https://www.ncbi.nlm.nih.gov/
Physical activity influences the immune system of breast cancer pubmed/?term=Impact+of+a+half+marathon+on+cellular+im
patients. J cancer Res Ther 3:392–398 mune+system%2C+pro-inflammatory+cytokine+levels%2C+a
Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, nd+recovery+behavior+of+breast+cancer+patients+in+the+a
Galvao DA, Pinto BM, Irwin ML, Wolin KY, Segal RJ, LuciaA, ftercare+compared+to+healthy+controls
13