Physical Activity and Breast Cancer Prevention: Possible Role of Immune Mediators

Abstract

There is strong evidence that physical activity (PA) reduces risk, recurrence, and mortality from breast cancer. Emerging data suggest that PA induces changes in inflammatory and immune mediators that may contribute to beneficial effects on breast cancer outcomes. Thus, the goal of this review was to evaluate the evidence linking the protective benefit of PA to modulation of immune responses in breast cancer. A literature search was conducted to identify studies that evaluated the impact of PA on tumor and immune outcomes in breast cancer patients and in mammary tumor models. Nineteen studies investigated the effect of PA interventions on cancer immune outcomes using preclinical breast cancer models. Tumor growth was reduced in 11 studies, unchanged in three studies, and increased in one study. Spontaneous metastasis was reduced in two studies and survival was improved in four studies. Frequently assessed immune outcomes include splenic cell number and function, circulating inflammatory cytokines, and intratumoral immune cells and inflammatory markers. Circulating inflammatory cytokine responses were heterogeneous in preclinical models. Within the tumor microenvironment (TME), several studies documented a change in the infiltration of immune cells with an increase in effector cells and a reduction in immune suppressive cells. Twenty-three studies investigated the effect of PA interventions on immune outcomes in breast cancer patients. Thirteen studies used aerobic PA interventions and 10 studies used a combination of aerobic and resistance exercise interventions. Cycling and treadmill activities were the most commonly used PA modalities. Circulating immune cells and inflammatory cytokines were the most frequently assessed immune outcomes in the clinical studies. Among the 19 studies that evaluated a PA intervention during the post treatment period, 10 reported a reduction in the levels of at least one inflammatory cytokine. No inflammatory cytokines were quantified in the three studies that evaluated a PA intervention during treatment with chemotherapy. Immune outcomes within the tumor were assessed in only one study performing a PA intervention prior to surgery. Results from preclinical and clinical studies suggest that PA exerts heterogeneous effects on inflammatory cytokines, but may alter the gene expression profile and immune infiltrates in the tumor which may result in a reduction in immunosuppressive factors. However, additional studies are needed to better understand the effect of PA on immune outcomes in the TME.

Keywords: exercise; immunity; inflammation; recurrence; survival.

Figure 1

Proposed immune mechanisms altered by physical activity that may play a role in reducing tumor growth, metastatic burden and mortality. Physical activity may modulate immune responses in circulation resulting in enhanced immune surveillance by increasing the number, activation status, and cytotoxicity of NK cells, enhancing CD4⁺ T cell proliferation and Th1 cytokine production, and reducing the number or percentage of immunosuppressive MDSCs and Tregs. Furthermore, physical activity may alter the immune landscape within the TME leading to greater infiltration of effector cells (CD4⁺ and CD8⁺ T cells, NK cells) concurrent with a reduction in immunosuppressive factors including IL-6, PD-1, and IDO, and less accumulation of MDSCs, TAMs, and Tregs. TME, tumor microenvironment; IL-6, interleukin-6; PD-1, programmed cell death protein 1; IDO, indoleamine 2,3-dioxygenase; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage; Treg, regulatory T cell.