Table.

Future Directions for Research Into the Effects of Exercise on Inflammation-Immune Axis Function in Cancer

Current Evidence		Future Directions
Exercise in Cancer Prevention
A. Chronic inflammation  Minimal evidence: Exercise is generally associated with decreases in inflammatory markers, both in preclinical and clinical studies; data vary depending on model/population/exercise dose. B. Immune surveillance  Minimal evidence: Exercise is generally associated with increased NK cell function in preclinical models; clinical data are inconclusive.		Exercise may directly influence the metabolic and immunologic mechanisms that foster a chronic state of smoldering inflammation.  Direct evidence for the mechanisms involved should be obtained in pre-clinical models of carcinogenesis, focusing on models of inflammation-driven carcinogenesis. Examples include: A mouse model of colitis-associated cancer induced using azoxy-methane/dextran sulfate sodium (AOM/DSS).[144] The transgenic mouse model of inflammation-associated de novo epithelial carcinogenesis using K14-HPV16 mice.[145] Since many of the mechanisms underlying cancer development in these models have been defined, they provide a straightforward platform for studying the effects of exercise on both protective and promoting immune effectors.
Exercise in Cancer Treatment
C. Immune escape and tumor progression		By comparing the response to treatment in immune-deficient and immunocompetent mice, it has been established that some chemotherapy drugs and radiotherapy work, at least in part, by activating antitumor immune responses.[146]
Innate immunity	Minimal evidence: Exercise may decrease TAM and TAN infiltration in preclinical models; no clinical evidence.
Adaptive immunity	Minimal evidence: Exercise may increase intratumoral cytotoxic T-cell infiltration and reduce Treg infiltration in preclinical models; no clinical evidence.	A similar approach could be used to determine whether exercise can reduce cancer growth and whether its effects require the presence of an intact immune system.
Exploring Exercise in Combination With Immunotherapy
D. Triggering an immune response  Minimal evidence: Exercise may increase DC number in preclinical models; no clinical evidence.		Because immunotherapy can achieve long-term responses superior to those seen with most other treatments, but works only in subsets of patients, combination treatments that enhance responses are under active investigation.  Exercise is likely to have benefits with limited side effects and could be easily explored in multiple well-defined mouse cancer models. Genetic tools are available to dissect the mechanisms involved, thus identifying potential biomarkers for testing in patients.[147]

DC = dendritic cell; NK cell = natural killer cell; TAM = tumor-associated macrophage; TAN = tumor-associated neutrophil; Treg = regulatory T cell.