201P - Role of aerobic exercise training on the mitochondrial metabolism and effector function of CD8+ tumor-infiltrating lymphocytes

Background

Immunotherapy provided a new treatment alternative for cancer, but many patients still do not respond due to tumor-induced immunological dysfunction. Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality and improve immune response, however the mechanisms explaining AET benefits immune system on cancer remain unclear. Thus, our aim was to evaluate whether AET could positively modify the tumor microenvironment, favoring infiltration and cytotoxicity of “antitumor” lymphocytes by regulating their mitochondrial content and function.

Methods

Balb/c male mice were submitted to 4 weeks of AET (60% of maximal capacity, 5 days/week, 1 h/day) before inoculation (s.c.,1x10⁶ CT26 colon carcinoma cells). CT26 TR continued AET after inoculation and all groups were euthanized 9 days post tumor cells inoculation for further analysis. Tumor volume was measured daily. Experimental groups were divided into control (healthy sedentary mice), CT26 SED (sedentary tumor-bearing mice) and CT26 TR (trained tumor-bearing mice). Tumor-infiltrated T lymphocytes and mitochondrial density were measured by flow cytometry. Tumor hypoxia was measured by Hypoxyprobe Kit. Mitochondrial morphology was evaluated by electron microscopy and ATP production by an ATP Determination Kit. Statistical analysis: Anova One-way, Duncan post hoc, p<0.05. Ethical approval: CEUA EEFE-USP 2017/02.

Results

CT26 TR mice showed attenuated tumor progression when compared with CT26 SED group, with significant smaller tumor volume and mass. AET significantly reduced tumor hypoxic area compared to CT26 SED group. AET significantly increased the total amount of activated and effector memory CD8⁺ T cells, and effector memory CD4⁺ T cells in CT26 TR when compared to CT26 SED in the tumor. Additionally, increased function of T CD8+ cells in CT26 TR was followed by a higher mitochondrial number/cell and function (ATP production) in this cells compared with CT26 SED group.

Conclusions

AET increases tumor-infiltrated cytotoxic/effector CD8+ T cells and improves their mitochondrial content and function. These data suggest that AET can attenuate tumor growth by modulation of tumor-infiltrated lymphocytes number and profile.

Legal entity responsible for the study

The authors.

Funding

São Paulo Research Foundation (FAPESP, 11800-4/2021, 2015/22814-5, and 2017/13133-0).

Disclosure

All authors have declared no conflicts of interest.