Can Exercise Boost Anticancer Immunity?

Cancer is one of the leading causes of death globally, with approximately 20 million new cases per year and around 10 million deaths in 2020 alone (Sung et al. 2021). Not only does cancer put a significant burden on the patients directly affected and their loved ones, but also on the healthcare system, with a projected global cost of $25.2 trillion between 2020-2050. So, what if some of this load could be lifted by a relatively inexpensive lifestyle change?

The Benefit of Feeling the Burn

The World Health Organization (WHO) estimates that around 30% to 50% of deaths caused by cancer could be avoided by modifying certain key risk factors. Thus, those of us whose New Year's resolution is to hit the gym more may feel vindicated to know that one of these modifying factors is the implementation of regular exercise, which has been shown to lower the incidence, recurrence, and mortality of cancer (Fluza-Luces et al. 2023). While this may not seem like a stretch, currently a staggering 4 in 5 adolescents and adults worldwide fail to meet the minimum guidelines stipulated by the WHO for both aerobic and muscle-strengthening activities (Garcia-Hermoso et al. 2023).

Various studies have indicated the benefits of exercise on cancer however the mechanisms driving these are still undefined. Although getting to the bottom of the precise means of protection can often feel like running in circles, one thing that is largely agreed upon is that it is the immune system that does the heavy lifting.

Keeping the Immune System on Its Toes

One of the reasons that cancerous cells are often able to survive and proliferate in the host is the crafty ability of the tumor to restrain the immune system that's been tasked to destroy it. Broadly speaking, this can be done either via the promotion of immunosuppressive factors or via the suppression of immune drivers.  

A recently identified subset of immature myeloid cells known as myeloid-derived suppressor cells (MDSCs) has been shown to accumulate in the tumor, owing to the chronic inflammation present in the tumor microenvironment (TME) which blocks their complete differentiation into macrophages, dendritic cells (DCs), or granulocytes (Fleming et al. 2018). These MDSCs can strongly suppress the cytotoxic functions of effector T cells and natural killer (NK) cells, key players in immune-mediated cancer defense. Not only that, but they also have the ability to induce regulatory T cells (Tregs), which further contribute to the immunosuppressive milieu of the TME (Kim and Cho 2022).

Infiltration of CD8 T cells and NK cells into the tumor is associated with a better prognosis in many types of cancer (Li et al. 2018, Melaiu et al. 2020). However, the tumor is often one step ahead and has yet again developed mechanisms to overcome this. For example, interferon gamma (IFNy) stimulates the expression of the chemokine receptor CXCR3 on CD8 T and NK cells, which mediates their recruitment to the site they are needed. Cancer cells have developed the capacity to reduce expression of CXCR3 ligands, such as CXCL9, CXCL10, and CXCL11, to block this migration. Cancer’s deviousness goes further, with the added ability to influence neighboring blood vessels to reduce adhesion molecules necessary for cell movement out of the vessel and into the tumor, ultimately reducing cytotoxic cell infiltration (Kim and Cho 2022).

So, with this in mind, what does exercise do to make cancers break a sweat?

A Workout for the Immune System

Multiple studies in both mice and humans have been carried out to investigate the effect of exercise on different cell types.

First, let’s focus on how exercise impacts the MDSCs. Two studies used a mouse model of breast cancer, induced via inoculation with 4T1 breast cancer cells in the mammary fat pad, exercised either by wheel running or treadmill running, and compared them to sedentary controls. Both studies independently found a reduction in MDSCs in the tumor in exercised mice relative to sedentary animals (Garritson et al. 2020, Wennerberg et al. 2020). Wennerberg et al. noted that the reduction in MDSCs was inversely proportional to the frequency of CD8 T cells, indicating a shift in balance between the suppression and activation of the immune response in tumors. Interestingly, they found that exercise also improved the response to anti-PD-1 treatment, a cancer therapy used to reinvigorate the weakened immune response (Wennerberg et al. 2020).

Additionally, Hagar et al. (2019) looked at the shift in the balance of suppressor and effector cells with exercise in the same mouse model of breast cancer. However, in this case, they focused on Tregs as their suppressor cell. By comparing exercised mice to sedentary controls, they found a twofold increase in the CD8 T cell to Treg cell ratio. Furthermore, they noted a 17% slower growth rate of tumors and 24% longer survival in exercised mice, which was not observed in exercised athymic mice, which lack mature T cells, indicating a key role of T cells in exercise-induced anticancer immunity (Hagar et al. 2019).

However, while Hagar et al. found that the change in the CD8 T cell:Treg ratio was due to a decrease in Treg number and not due to a change in CD8 T cell numbers, Gomes-Santos et al. (2022) saw the opposite, with no changes in the number of Tregs but a significantly increased CD8 T cell number upon exercise. Moreover, by exercising mice lacking CXCR3, they found that the higher CD8 T cell numbers were dependent on this chemokine signaling pathway, indicating that exercise increases CD8 T cell infiltration into the tumor (Gomes-Santos et al. 2021). 

Not only has exercise been shown to induce CD8 T cell mobilization, but also NK cell infiltration into the tumor. Pederson et al. were able to demonstrate this effect in multiple different tumor models, including two melanoma models (either driven by subcutaneous inoculation with B16F10 cells or using the Tg(Grm1)EPv mouse that spontaneously develops melanoma), a liver carcinoma model, and a lung carcinoma model (Pederson et al. 2016). Remarkably, increased CD8 T cell and NK cell infiltration into the tumor has also been seen in human pancreatic cancer patients prescribed aerobic activity (Kurz et al. 2022, Djurhuus et al. 2023).

While further research is required, it appears that the ability of exercise to stimulate the immune response to either prevent or ameliorate cancer, or even to aid in the response to anti-PD-1 treatment, is an enticing therapeutic option. Not only is exercise a cheaper alternative, but it is also not associated with the detrimental side effects often present with chemotherapeutic drugs and has no excess risk at over ten times the minimum recommended activity amount (Arem et al. 2016). If that isn’t good motivation to get on your gym gear and trainers and start moving, then I don’t know what is!