Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?

Abstract

The immune system plays an important role in controlling cancer growth. However, cancers evolve to evade immune detection. Immune tolerance and active immune suppression results in unchecked cancer growth and progression. A major contributor to immune tolerance is the tumor physiologic microenvironment, which includes hypoxia, hypoglucosis, lactosis, and reduced pH. Preclinical and human studies suggest that exercise elicits mobilization of leukocytes into circulation (also known as "exercise-induced leukocytosis"), especially cytotoxic T cells and natural killer cells. However, the tumor physiologic microenvironment presents a significant barrier for these cells to enter the tumor and, once there, properly function. We hypothesize that the effect of exercise on the immune system's ability to control cancer growth is linked to how exercise affects the tumor physiologic microenvironment. Normalization of the microenvironment by exercise may promote more efficient innate and adaptive immunity within the tumor. This review summarizes the current literature supporting this hypothesis.

Figure 1.

Exercise primes the tumor toward a more aerobic, less glycolytic physiologic microenvironment. The schematic demonstrates the large-scale vascular (top) and microscale physiologic microenvironment (bottom) changes within the tumor of an exercised versus sedentary individual. It is not drawn to scale. Exercise, in normalizing tumor vasculature, increases endothelial adhesion molecule expression, promotes the extravasation of cytotoxic immune cell (NK cells, CD8⁺ T cells, and type 1 macrophages) and infiltration of these cells into the tumor. Conversely, under the sedentary condition, tumors manifest a hypoxic, aberrantly vascularized, and highly glycolytic tumor. The two tumor cross-sections on the bottom represent the physiologic microenvironment of a sedentary versus exercised individual. High lactate, low pHe, and hypoglucotic environment within the sedentary tumor promote immune-suppressive Tregs but inhibit the function of tumor-infiltrating cytotoxic immune cells. The immune cells that are in the sedentary tumor microenvironment are metabolically outcompeted by the highly proliferative cancer cells. Exercise, by normalizing tumor vasculature, yields a better perfused tumor, with improved energy substrate (glucose availability), improved oxygen concentrations, and decreased glycolytic lactate production. The net effect of this is an enhanced metabolic and immunologic environment, one that results in more potent immune activation and more effective tumor cell cytolysis.