Exercise and the Lung Cancer Tumor Microenvironment

Background

Lung cancer continues to be the most common cause of cancer related death in both men and women. Patients have variable responses to treatment, whether they receive neoadjuvant therapy or surgery alone. Many of these variations can be attributed to known patient risk factors including age, smoking status, and BMI. However, there are more complex pathophysiologic factors that affect how patients respond and recover from all insults, including cancer.

Lung cancer resides in a complex milieu known as the lung tumor microenvironment (TME). The TME includes the cellular makeup of the tumor as well as factors such as IL6, PDL1 ligand, COX2, PGE2, and other cytokines. These factors can cause the TME to change in states of inflammation, such as COPD, and impact carcinogenesis (1-3). Thus, it is reasonable to assume that other physiologic alterations can change the TME. These physiologic states may be alterable and could be used to improve the efficacy of targeted therapies.

The innate and adaptive immune cells in the lung TME harbor tumor promoting and suppressing activities, which may affect clinical outcomes. Cancer associated fibroblasts (CAF) isolated from human lung cancer tissues have been shown to secrete interleukin-6 (IL-6), which then stimulates Janus kinase 2(JAK2)-signal transducers. Through this mechanism, transcription 3 (STAT3) signaling is activated and ultimately leads to increased metastasis in vivo. CAFs modulate multiple immune pathways in the TME, as they also express PDL1 to blunt activation of T cells and cross present antigens to eliminate antigen-specific CD8+T cells via PDL2 and FASL. CAFs have been found to be indicators of poor prognosis, associated with nodal metastases and increased risk of recurrence (6).

Physical fitness and moderate intensity exercise training have been shown to improve immune responses to vaccination, reduce chronic low-grade inflammation, and improve various immune markers in several disease states including cancer, HIV, cardiovascular disease, diabetes, cognitive impairment, and obesity (4). In mouse models, exercise has been shown to decrease tumor incidence and growth by over 60% (5). Prior work by Simpson and colleagues have shown that even a single bout of aerobic exercise greatly increases NK cell and γδ T cell numbers as well as increases the proportion of total lymphocytes found in the peripheral blood. Exercise can also increase the number of cytotoxic T cells in the blood without increasing their proportion of total lymphocytes.