The potential role of exercise and nutrition in harnessing the immune system to improve colorectal cancer survival

Colorectal cancer (CRC) is the third most common cancer and third leading cause of cancer death in both men and women in the U.S. Given the recent decline in both incidence and mortality due to advances in early detection and treatment, the number of Americans living with CRC, which is estimated to be almost 1.5 million as of 2016, is likely to increase dramatically over the coming decades. CRC survivors are at high risk for a recurrence, new primary cancer, metastasis, as well as treatment-related adverse effects. Development of new approaches to improve patients’ long-term survival outcomes is a high priority.

Recently, strategies targeting the immune system have gained great attention, mainly owing to the durable responses demonstrated by immune checkpoint inhibitors in many patients with advanced malignancies, including CRC. Although application of these treatments remains relatively limited, the striking success of immunotherapies in specific clinical circumstances has motivated research to identify novel strategies based on immune modulation to more effectively harness the immune system to combat cancer. CRC is a particularly good candidate for this line of research because of the established relationship of immune and inflammatory mechanisms with CRC, as indicated by the known role of inflammatory bowel disease in the etiology of CRC and the chemopreventive effect of anti-inflammatory agents such as aspirin against CRC.

Indeed, substantial data support the prognostic significance of the tumor immune microenvironment for CRC. Likewise, increasing evidence indicates that host factors, such as diet and lifestyle, can also have a considerable influence on CRC prognosis and that these effects are, at least partly, mediated by alterations in tumor immunity. In support of the importance of the interaction between extrinsic factors and host immunity in CRC, growing data indicate that the gut microbiota, which is shaped mainly by diet and lifestyle, plays a critical role in the intestinal and systemic immune response, affects CRC incidence and progression, and predicts responsiveness to immunotherapy. Therefore, these lines of evidence collectively support the need for further research into the interplay between environmental factors and tumor immunity for CRC survival. The resultant findings may not only help refine current supportive care guidelines for CRC survivors, but also may lead to development of safe, cost-effective adjuvant therapies based on lifestyle modification to optimize the benefit of immunotherapies and other treatment modalities. Herein, we review the most recent data regarding how exercise and certain nutritional factors may improve CRC survival via immune and microbial mechanisms (Figure 1), and identify critical questions for future research.

Figure 1.

Potential immune and microbial mechanisms underlying the benefit of exercise and nutritional factors for colorectal cancer survival. In addition to the local effects, these lifestyle factors also reduce systemic inflammation induced by cancer and treatment. CCL2, C-C motif chemokine ligand 2; HDAC, Histone deacetylase; MDSC, myeloid-derived suppressor cells; NK, natural killer; PGE₂, Prostaglandin E₂; SCFA, short-chain fatty acid; TCR, T cell receptor; Treg, regulatory T cells.

Role of the immune system in CRC survival

Spanning the evolution of the earliest concept of cancer immunosurveillance proposed by Paul Ehrlich in the 1950s to the cancer immune-editing concept elucidated by Schreiber and colleagues in 2002, in the last several years, the field has grown to recognize a dual role of the host immunity, both as an extrinsic tumor suppressor and a facilitator of tumor growth and progression.¹ In parallel, while early clinical data have focused on the beneficial effect of the adaptive immune response (e.g., tumor-infiltrating cytotoxic and memory T cells and T helper 1 cells [Th1]) for CRC survival, more recent data indicate the functional heterogeneity of certain immune cells (e.g., Th17 cells² and regulatory T cells [Tregs]³) in CRC depending on the immune and microbial context, as well as the importance of the balance between cytotoxic T-cell lymphocytes and immune checkpoint expression in the prognosis of CRC.⁴ These data highlight the plasticity of an immune system that may be modified to both activate anti-tumoral immunity and suppress immune evasion by tumors.

Exercise

Several observational studies have consistently identified a dose-dependent relationship between physical activity, both before and after CRC diagnosis, and lower risk of recurrence and mortality.⁵ Moreover, CRC patients who increased their physical activity by any level from pre- to post-diagnosis showed decreased mortality compared with those who did not change their physical activity level or were inactive/insufficiently active before diagnosis. In addition, clinical evidence indicates the benefit of exercise for improving the efficacy of radiotherapy and chemotherapy as well as reducing cancer- and treatment-related adverse effects, including cachexia, depression, anxiety, and cognitive problems. Preliminary results of a multicenter randomized controlled trial (RCT) indicate the feasibility of a structured exercise program in colon cancer survivors and the benefit of 1-year intervention for a variety of health-related fitness parameters.⁶

Regarding the mechanisms, exercise may regulate tumor growth kinetics and metabolism through both physical (e.g., increased blood flow, shear stress on the vascular bed, and sympathetic activation) and endocrine (e.g., stress hormones and myokines) mechanisms. These effects may also contribute to exercise-induced enhancement of antitumor immunity by increasing mobilization and infiltration of innate and cytotoxic immune cells in the tumor microenvironment. For example, a recent study revealed that exercise increased accumulation of natural killer (NK) cells in an epinephrine- and interleukin (IL)-6-dependent manner, thereby decreasing tumor growth by over 60% across different mouse tumor models.⁷

Moreover, given the close link between tumor metabolism and immunity, physical activity may also regulate tumor immunogenicity by reducing production of metabolic byproducts. For instance, exercise has been shown to lower intratumoral levels of lactate, a byproduct of aerobic glycolysis that is enhanced in most tumors due to metabolic reprogramming. Lactate may facilitate tumor growth through its immunosuppressive effects, including impaired activity of NK and T cells, disrupted T cell motility, and increased tumor-permissive activity of tumor-associated macrophages.

In addition, exercise may improve immune and metabolic homeostasis by modifying the gut microbiota. Compared to healthy controls with similar body mass index, professional athletes have been found to have a more diverse fecal microbiota and enrichment of metabolic pathways related to production of secondary metabolites with immune benefits, such as short-chain fatty acid (SCFA).⁸ SCFA, including butyrate, acetate and propionate, is a family of bacterial fermentation products of fiber and functions as a critical regulator of colonic Treg homeostasis and expression of numerous genes responsible for tumor growth and migration.

Finally, exercise may also improve systemic immunity and metabolic health of cancer patients through reductions in systematic low-grade inflammation, as indicated by lower levels of pro-inflammatory factors (e.g., C-reactive protein, tumor necrosis factor alpha) in clinical intervention studies.

Marine omega-3 fatty acid (MO3FA)

Higher MO3FA intake after CRC diagnosis has been associated with lower risk of recurrence and overall and CRC-specific mortality.^{9, 10} Patients who increased their intake of MO3FA after diagnosis had a particularly longer survival than those who did not change or reduced their intake. The beneficial effect of MO3FA on CRC survival is supported by a RCT demonstrating that MO3FA supplement of 2 g daily prior to surgery reduced mortality among patients with CRC liver metastasis.¹¹ In addition, some clinical evidence indicates the benefit of MO3FA for abrogation of cancer cachexia, although the RCT data remain inconclusive.

The anticancer effect of MO3FA may be related to its anti-inflammatory activity mediated by increased incorporation of these fatty acids into cell membranes at the expense of arachidonic acid and alterations in lipid raft structure and function. These changes decrease the production of inflammatory eicosanoids (e.g., prostaglandin E₂) and chemokines (e.g., C-C motif chemokine ligand 2), reverting the immune suppression mediated by Tregs and myeloid-derived suppressor cells to enhance antitumor immunity. In support of these mechanistic data, our recent cohort study indicated that high intake of MO3FA was associated with lower risk of CRC that is infiltrated with high density of FOXP3⁺ T cells, but not tumors with low FOXP3⁺ T cells.¹² FOXP3 is a prerequisite transcription factor for the immunosuppressive function of Tregs. Consistent with the human findings, our in vitro study indicated that MO3FA treatment decreased the suppressive activity of Tregs against proliferation of T effector cells. This effect may be mediated by alterations in the Treg cytokine repertoire (e.g., lowering inhibitory cytokine IL-10) and the gut microbiota.

Compared to other fats, MO3FAs have been associated with higher intestinal microbiota diversity and amelioration of ⍵−6 fatty acid- or antibiotic-induced dysbiosis. MO3FA supplementation has been shown to increase the abundance of anti-inflammatory bacteria, such as SCFA-producing bacteria (mainly Lactobacillusand Bifidobacteria), and decrease the abundance of pro-inflammatory and tumor-permissive bacteria, such as lipopolysaccharide (LPS)-producing bacteria (e.g., Escherichia coli) and Fusobacterium nucleatum.¹³ LPS is a known trigger of chronic inflammation that may in turn promote CRC, while F.nucleatum may support CRC development and metastasis by potentiating tumoral immune evasion, inhibiting anti-tumor defense by NK or T cells, and modulating E-cadherin/β-catenin pathway. On the other hand, commensal bacteria Bifidobacteria have been found to improve the efficacy of programmed death-ligand 1 (PD-L1) blockade immunotherapy by modulating activation of dendritic cells and enhancing CD8⁺ T-cell immune response.¹⁴ These experimental and clinical data together support the potential of adjuvant or combinational treatment with MO3FA to improve CRC survival by abrogating immunosuppression and improving antitumor immune response.

Vitamin D

Higher pre- and post-diagnosis levels of circulating 25-hydroxyvitamin D have been consistently linked to improved survival among CRC patients across different stages.¹⁵ These observational data have been supported by a recent phase II RCT reporting the benefit of high-dose vitamin D treatment for progression-free survival among patients with metastatic CRC.¹⁶

Vitamin D regulates transcription of numerous genes by binding to and activating the nuclear vitamin D receptor (VDR), thereby exerting a wide spectrum of anticancer activities, including anti-proliferation, induction of differentiation and apoptosis, suppression of angiogenesis, and anti-inflammation. Among these mechanisms, the immunomodulatory effects of vitamin D are particularly compelling, due to the capability of immune cells for local synthesis and metabolism of bioactive vitamin D as well as the identified benefits of vitamin D for a variety of autoimmune and infectious diseases. Expressed in various immune cells, VDR mediates vitamin D signaling to modulate both innate and adaptive immune responses, including regulation of Th1/Th2 cell activity, interference with maturation and differentiation of dendritic cells, reduction of Treg proliferation, and control of T cell antigen receptor signaling to diminish the risk of immunopathology associated with explosive T cell proliferation. These data collectively support a role for vitamin D as a critical modulator for immune homeostasis. This may be particularly relevant to CRC because the large intestine is under constant exposure to chemical and bacterial carcinogens. Indeed, high vitamin D diet has been shown to reduce cancer incidence in a mouse model of bacteria-driven colitis and colon cancer,¹⁷ and vitamin D supplementation reduces tumor-promoting inflammation in RCTs. Moreover, we recently reported that the beneficial association of high vitamin D with lower risk of CRC was particularly strong for tumors with intense immune reaction and high infiltration of CD3⁺ T cells,¹⁸ supporting a role of vitamin D in cancer immunoprevention through tumor-host interaction. In line with the immunomodulatory effect of vitamin D, a genome-wide host-microbiota association study recently identified variants in the VDR gene among the most significant loci that were associated with overall gut microbial variation and abundance of individual bacteria as well as functions of gastrointestinal and immune-related tissues and cells.¹⁹

Fiber

We recently reported that higher postdiagnosis intake of dietary fiber, particularly that from cereals, and whole grains was associated with better CRC survival. Patients who increased their fiber intake after diagnosis from levels before diagnosis experienced substantially improved survival.²⁰ These findings suggest that the effect of high fiber intake may extend beyond protection against CRC incidence and contribute to better prognosis after cancer is established.

Besides the metabolic benefits on improved insulin sensitivity and lipid profile, fiber also possesses modulatory effects on systemic and local immunity. High fiber or whole grain diet has been shown to lower circulating inflammatory markers. Moreover, soluble fiber can be fermented by gut bacteria into SCFAs, which have been implicated in regulation of the intestinal immune responses and protection against CRC.¹³ As a major energy source for normal colonocytes, butyrate is metabolized to a lesser extent in CRC cells due to the Warburg effect and accumulates in the nucleus to epigenetically downregulate expression of numerous cancer-related genes by suppression of histone deacetylase (HDAC). Interestingly, as a group of FDA-approved chemotherapy agents, HDAC inhibitors demonstrate synergistic effects with immunotherapy based on PD-1 blockade to promote T-cell infiltration and enhance tumor-infiltrating T-cell function,²¹ providing the rationale for studying the role of butyrate in immunotherapy. Moreover, butyrate has been shown to interact with G protein-coupled receptors to promote anti-inflammatory properties of colonic macrophages and dendritic cells, thereby inducing differentiation of Tregs. These effects may be important for host tolerance to intestinal microbiota and maintenance of immune homeostasis. Indeed, administration of fiber has been shown to prevent western diet-induced defects in the colonic mucus layer by enrichment of Bifidobacteria that has potential anti-inflammatory and anti-CRC properties.²²

Coffee

Two recent prospective studies have linked higher consumption of coffee after CRC diagnosis to lower recurrence and improved survival.^{23, 24} This is in line with the reported benefit of habitual coffee consumption for metabolic regulation, type 2 diabetes, cardiovascular diseases, liver diseases, all-cause mortality, and incidence of several cancers, including CRC. Phytochemical compounds contained in coffee (e.g., diterpenes, melanoidins, and polyphenols) are known antioxidants and may prevent malignant transformation and growth of cells. Moreover, various polyphenols found in coffee (e.g., chlorogenic acid) have been suggested to have antiproliferative, proapoptic, antiangiogenic, and antimetastatic effects. In addition, the anti-inflammatory activity of caffeine and other components in coffee has been recognized and higher coffee consumption has been linked to lower levels of circulating chemokines and cytokines, although the effects of coffee on the local tumor immunity remain to be elucidated. Moreover, a recent population-based metagenomics analysis identified coffee as one of the top dietary factors that are associated with the increased diversity of the gut microbiota, suggesting the benefit of coffee for host-microbial interactions.²⁵

Future directions and concluding remarks

Despite substantial evidence supporting the importance of diet and lifestyle for CRC incidence,²⁶ until recently very little has been known about their influence on survival of patients with established cancer. This is an urgent question to address because the number of patients living with CRC continues to rise. Moreover, the potential impact of lifestyle interventions is particularly great among cancer survivors since, compared to cancer-free individuals, these patients are more likely to benefit given their higher prevalence of cancer risk factors, such as obesity, physical inactivity and unhealthy diets, and are also more motivated to adhere to strategies to facilitate their treatment and recovery. While most of the existing evidence has been limited to observational studies, preliminary data from RCTs also support the benefit of exercise and supplementation of marine omega-3 fatty acid and vitamin D among CRC patients, providing the rationale for further larger validation trials. On the other hand, mechanistic data remain very limited, particularly regarding the interaction with the host immune system. Further studies are needed to investigate how these extrinsic factors may influence tumor-associated immune responses and predict the efficacy of immunotherapy, preferably through well-designed biomarker trials and by leveraging primary treatment trials; how diet, in conjunction with the gut microbiota, may shape and interact with the tumor immune microenvironment to influence tumor growth and distant metastasis; and how the lifestyle-based strategies may synergize with other anti-cancer therapies (e.g., immunotherapy and surgery) to lower post-operative morbidities and optimize treatment efficacy. Clearly, addressing these questions requires a multidisciplinary collaborative effort across the continuum of translational research.