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Immunotherapy in cancer treatment

This is an excerpt from Physical Activity Epidemiology-3rd Edition by Rodney K. Dishman,Gregory W. Heath,Michael D. Schmidt & I-Min Lee.

Immunotherapy tries to boost the immune system so it is better at targeting and killing tumor cells. Approaches include vaccinating against tumor antigens; amplifying activated T and B cells; and infusing interleukins (e.g., T cell growth factor [i.e., IL-2]) to raise levels of T cells and NK cells and other cytokines (e.g., INFα) to activate NK cells and dendritic cells. The local microenvironment of a tumor (e.g., immune cells, angiogenic cells, lymphatic endothelial cells, and cancer-associated fibroblasts) modulates cancer growth and progression (see figure 13.17). It can either inhibit or facilitate tumor proliferation by influencing local resistance to growth, interactions between cancer cells and the immune system, and the formation of metastases (Anari, Ramamurthy, and Zibelman 2018).

Immune cells and their cytokines have different roles before and after the establishment of a tumor, which can either enhance or impair clinical outcomes of immunotherapy. For example, immune cells such as NK cells and tumor necrosis factor can eliminate abnormal cells before they progress to a tumor. However, after tumor establishment, the microchemical environment of tumor cells modulates the function of immune cells. During an immune-escaping phase of tumor growth, the antigenic immune response is either inadequate or focused entirely on tolerance, or the tumor is not recognized by the immune system as foreign (Upadhyay et al. 2018).

After extravasation into a tumor, cytotoxic T cells are in a microenvironment rich in tumor-associated immunosuppressive cells including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory cells (Tregs), and cancer-associated fibroblasts, which release molecules that inhibit or kill the T cell by apoptosis (Martinez and Moon 2019). See figure 13.18.

Tumors prefer glucose as fuel, and the hypoxia that accompanies glycolysis restricts oxidative phosphorylation that is necessary for memory T cells. Tumor cells produce reactive oxygen species (free radicals) that can kill T cells. Tumors and tumor-associated cells also secrete VEGF, tumor growth factor, and prostaglandin E2, which impair T cells. New therapies that combine the use of inhibitors of checkpoint proteins that turn off T cell recognition of a tumor, armored CARs (e.g., modified to secrete cytokines such as IL-12) that defeat the immunosuppressive tumor environment, and suppression of other inhibitory factors in the tumor microenvironment can boost CAR T cell success in solid tumors and are being tested in clinical trials (Martinez and Moon 2019).

Cancer immunotherapy has advanced by the use of chimeric antigen receptor (CAR) T cells, which are engineered to express synthetic receptors that direct T cells to surface tumor antigens. CARs are designed to augment T cell activity and for persistence in killing target tumors. They have been successful against so-called liquid tumors (e.g., hematologic malignancies such as leukemias) but have yet to have similar success for treating solid tumors (Kosti, Maher, and Arnold 2018; Newick et al. 2017). Barriers to success in treating solid tumors include low accumulation of CAR T cells in the tumor because of poor trafficking or physical exclusion and the exposure of infiltrating CAR T cells to immune suppressive checkpoint molecules, cytokines, and metabolic stresses that are not conducive to efficient immune reactions (Kosti, Maher, and Arnold 2018). Treatment innovations to genetically reengineer CAR T cells to counter inhibitory influences found in the tumor microenvironment and new immunotherapy drug combinations are being considered as ways to augment the activity of CAR T cells (Kosti, Maher, and Arnold 2018).

Physical Activity and Immunity: The Evidence

After the German physiologist G. Schulz (1893) reported that muscle activity produced an increase in the number of leukocytes in the blood, severalfold increases in blood leukocytes were reported in four men after they ran the Boston Athletic Association’s marathon of 1901 (Larrabee 1902) and in another group of men after a 400 m race (Garrey and Butler 1929). Lymphocytes increased in number within the first 10 min of exercise, and this was followed by an increase in neutrophils—the same pattern seen after an injection of epinephrine. Hence, it was hypothesized that an increase in epinephrine levels during exercise was responsible for leukocytosis during exercise (Martin 1932). Modern studies have generally confirmed those early observations of leukocytosis in response to exercise (Pedersen and Hoffman-Goetz 2000; Woods, Ceddia et al. 1999; Woods, Lowder, and Keylock 2002).

Acute Exercise

Among normal, healthy people, the numbers of several types of immune cells, especially NK cells and neutrophils, are usually elevated during and immediately after a session of moderate- to high-intensity exercise (50%-85% V.O₂max; Fiatarone et al. 1988; Lewicki et al. 1988; Moyna et al. 1996; Murray et al. 1992; Palmo et al. 1995; Rhind et al. 1999). Neutrophils remain elevated for several hours, and lymphocytes return to normal levels within 2 h (Lewicki et al. 1988) to 24 h after the exercise (Espersen et al. 1996). However, after heavy, prolonged exercise, numbers of lymphocytes and NK cells can be depressed below normal levels for up to 6 h (Espersen et al. 1996). One view is that this period of immunosuppression after heavy exercise provides a window of susceptibility to infection if exposure to a pathogen occurs while the number of cytotoxic cells is below normal (Hoffman-Goetz and Pedersen 1994).

Macrophages

Acute exercise increases the number of monocytes circulating in the blood. This increase in monocytes (as for other leukocytes) is best explained by an influx of cells from the marginal pool. Exceptions to this increase are the migration of monocytes from the blood during prolonged exercise of several hours and a likely increase in the region of an infection after exhaustive exercise. The latter exception makes sense, as a localized infection would logically have higher biological priority than would circulatory adjustments during exercise. Exercise also has stimulatory effects on phagocytosis, antitumor activity, reactive oxygen and nitrogen metabolism, and chemotaxis of macrophages, but most of the studies that investigated these effects used mice rather than humans as subjects (Woods, Davis et al. 1999). Studies of mice also have shown that exercise training can increase macrophage antitumor activity, regardless of age. However, not all macrophage functions are enhanced by exercise. Reductions in the expression of MHC II by macrophages and in their antigen-presenting capacity have been reported. Hence, it has been suggested that exercise temporarily increases the phagocytic function of macrophages while inhibiting their accessory cell functions (Woods et al. 2000).

Lymphocytes

Many studies have suggested that the ability of T and B lymphocytes to proliferate (i.e., to grow and to reproduce by cloning) is increased when they are exposed to some mitogenic factors (factors that induce clonal expansion by lymphocytes, e.g., IL-2 and pokeweed) and inhibited when they are exposed to other mitogenic factors (e.g., phytohemagglutinin and concanavalin A). However, it appears that those changes mainly reflect the number of lymphocytes circulating in the blood during and immediately after exercise, not a real change in the growth and division of individual lymphocytes (Pedersen and Hoffman-Goetz 2000) (table 13.1). Entry of lymphocytes into the blood (i.e., lymphocytosis) during acute exercise seems to mainly depend on the release of catecholamines (i.e., norepinephrine from sympathetic nerves and epinephrine from the adrenal gland). Cytotoxic T (CD8⁺) lymphocytes, especially effector-memory T cells (Simpson et al. 2007), are more responsive to exercise than helper T (CD4⁺) or B lymphocytes, probably because they have more β₂-adrenoreceptors and adhesion molecules on their surface that respond to catecholamines and aid their removal from the marginal pool.

Within an hour or so of the end of an exercise session, lymphocyte numbers in the blood, especially NK cells, paradoxically fall below their preexercise levels (lymphocytopenia), possibly because of increased levels of cortisol from the adrenal cortex. Several hours later, but within 24 h, blood lymphocyte counts return to normal. A decrease in mitogen-stimulated T cell proliferation and T cell release of IL-2 and IFN-γ has been reported immediately after intense exercise (Gleeson and Bishop 2005).

Natural Killer Cells

A quantitative review of 27 published studies conducted on a total of 390 people indicated that the cumulative effect of acute exercise was an increase in NK cytotoxicity (i.e., the killing of tumor cells in vivo by NK cells) of 1.2 standard deviations (95% confidence interval [CI]: 0.37-2.1; Hong and Dishman 2004). Results changed distinctly over time, with a marked increase in cytotoxicity during and soon after exercise, a decrease below preexercise basal levels 1 to 3 h after exercise, and a return to the basal level within 24 h. Changes did not differ according to the mode or intensity of the exercise but were larger for exercise that lasted between 20 min and 2 h than for exercise longer than 2 h (e.g., Espersen et al. 1996; Nielsen et al. 1998; Rhind et al. 1999). Changes were larger among people who were either sedentary or physically active in their leisure but had not undergone exercise training designed to increase their physical fitness. The changes in NK cytotoxicity after exercise are probably more the result of changes in the number of NK cells in the blood than of changes in the ability of individual NK cells to lyse tumor cells. For example, most studies have found that when cytolytic activity of NK cells in the blood is appropriately expressed relative to NK cell number, it is not changed by exercise (Moyna et al. 1996; Nieman, Henson et al. 1995; Palmo et al. 1995), except when intense, unusual, and prolonged exercise can depress the cytolytic activity of NK cells for several hours (Gleeson and Bishop 2005).

Levels of prostaglandins (e.g., PGE2), β-endorphin, and catecholamines have been investigated as possible mechanisms or mediators of altered NK cell activity after acute exercise (Fiatarone et al. 1988; Moyna et al. 1996; Murray et al. 1992; Rhind et al. 1999), but there are too few studies using uniform methods to allow drawing conclusions. Some evidence indicates that the activity of neutrophils, including chemotaxis, phagocytosis, and the oxidative burst, is enhanced after moderate-intensity exercise, especially in the upper airways.

Eccentric Muscle Contraction

Eccentric resistance exercise involving smaller muscle groups has been found both to increase (Palmo et al. 1995) and to decrease (Malm, Lenkei, and Sjodin 1999) NK cell numbers in the blood circulation during exercise. In addition, the number of NK cells increases after a heavy exercise bout (80% V.O₂max) but not after light exercise (40% V.O₂max) (Strasner et al. 1997). Other studies have shown that prolonged endurance exercise (e.g., 2-3 h) and shorter term, heavy eccentric exercise can induce an inflammation-like response resulting in increased secretion of inflammatory cytokines (e.g., IL-1, IL-6, and TNF-α) by stimulating the liver’s biosynthesis of acute-phase proteins. Also, neutrophils and macrophages migrate to the area of muscle damage to remove the debris of dead cells.

Exercise Training

Evidence suggests that exercise training can mobilize and activate cytotoxic cells, restrict inflammatory signaling pathways’ immune cells derived from bone marrow, and modulate acute and chronic inflammation (Hojman 2017). However, too few studies of the effects of chronic exercise on macrophages, neutrophils, and T and B lymphocytes have been conducted to allow conclusions about the adaptations of these immune cells to repeated physical activity (Woods, Davis et al. 1999). Results are somewhat clearer for NK cells, which are perhaps the most responsive immune cell to acute exercise in humans. A half-dozen exercise training studies and another handful of cross-sectional comparisons between exercise-trained and untrained people showed a cumulative mean increase in numbers of NK cells of 0.6 standard deviations (95% CI: 0.3-0.9) and 1.0 standard deviation (95% CI: 0.7-1.4), respectively (Hong and Dishman 2004).

Results of individual studies have not consistently shown significant changes in NK cell activity, however (Shephard and Shek 1999). No change in NK cell activity or in blood mononuclear cell numbers or proliferation was found in 18 rheumatoid arthritis patients after eight weeks of progressive cycle exercise training (Baslund et al. 1993). Neither 12 to 15 weeks of a walking exercise program (45 min at 60%-75% maximal heart rate, five days per week; Nieman, Nehlsen-Cannarella et al. 1990) nor eight weeks of a combination of aerobic and resistance training (Scanga et al. 1998) influenced NK cell activity or circulating levels. Six months of aerobic exercise by elderly men and women did not significantly affect NK cell activity or leukocyte counts (Woods, Davis et al. 1999). In contrast, a cross-sectional study by Rhind and colleagues (1994) showed that physically trained individuals (with V.O₂max of 57 ml · kg⁻¹ · min⁻¹) had higher levels of circulating total leukocytes, granulocytes, and NK cells than previously untrained control individuals (V.O₂max of 39 ml · kg⁻¹ · min⁻¹).

Compared with the evidence from human studies, evidence of the effect of exercise training on NK cell cytotoxicity in mice has been more consistent. An hour and a half of daily, moderate-intensity swimming for 20 days increased NK cell activity in mice (Ferrandez and De la Fuente 1996). Hoffman-Goetz, Arumugam, and Sweeny (1994) conducted a series of studies on NK cell activity and tumor metastasis following exercise training in mice. After nine weeks of wheel running and treadmill training exercise, male C3H mice were injected with tumor cells. After three weeks of tumor development and no exercise, the mice were killed. Trained mice demonstrated enhanced splenic NK cell activity and lower tumor cell retention in the lungs (MacNeil and Hoffman-Goetz 1993b). Treadmill training for 10 weeks enhanced NK cytotoxicity in mice measured in vitro (Simpson and Hoffman-Goetz 1990), and nine weeks of both voluntary wheel running and treadmill training resulted in increased cytotoxicity both in vivo and in vitro (MacNeil and Hoffman-Goetz 1993a). A dissociation between NK cytotoxicity and tumor metastasis was found in female mice that received an injection of tumor cells; mice with previously elevated activity of NK cells activated by lymphokines measured in vitro showed higher tumor multiplicity after eight weeks of voluntary wheel running (Hoffman-Goetz, Arumugam, and Sweeny 1994).

In contrast to findings from studies of mice, basal splenic NK cell activity in rats did not change after six weeks of voluntary wheel running (Dishman et al. 1995), six weeks of treadmill running (Dishman, Warren et al. 2000), or 15 weeks of treadmill running (Nasrullah and Mazzeo 1992). Conversely, reduced immune functions including NK cell activity in obese Zucker rats were restored after treadmill exercise five days per week for 40 weeks (Moriguchi et al. 1998).

The balance of the evidence in humans and in rodents is that chronic physical activity does not alter basal NK activity, despite a temporary enhancement of NK cytotoxicity right after an exercise session. However, other studies in rats indicate that chronic physical activity, independently of any fitness changes, protects against the suppression of NK cell activity after stress (Dishman et al. 1995; Dishman, Hong et al. 2000, Dishman, Warren et al. 2000.

Investigators have not always clearly described the use of force in studies of swimming and treadmill running and have used various strains of rats and mice that differ in their inherent running behavior. Hence, it remains important to determine the effects of chronic exercise independently of the co-occurring stress of forced, rather than voluntary, exercise. Although exercise training has been found to augment NK cell activity in rats and mice, it has not been shown whether exercise training enhances peripheral blood NK cytotoxicity in humans. The insignificant effect of exercise training on resting NK cell activity observed in human studies raises questions regarding the nature of the exercise program (its intensity, duration, etc.) as it might affect different adaptations in NK cell activity. Also, there are at least two distinct subsets of human NK cells based on the expression intensity of CD56: CD56(bright) and CD56(dim) cells. During exercise, CD56(dim) cells are more responsive, but up to 1 h of recovery after exercise, CD56(bright) cells are more responsive, which may have implications for the use of exercise as an adjuvant in the treatment of inflammatory diseases such as MS (Timmons and Cieslak 2008).

Table 13.2 summarizes the effects of acute and chronic exercise training on the immune system.

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