Berries and their phytochemicals have well documented chemopreventive roles, but understanding their ability to regulate cancer immunology is only beginning to be explored. The literature, including human studies, suggests that berry components can modulate our immune system to delay cancer development. Moreover, their wide spectrum of phytochemicals suggests that they might influence the functions of multiple immune cells and different aspects of cancer immunity. Cancer immune-therapies are showing promise for some types of cancer because they boost T cells’ ability to recognize tumor cells – an essential prelude to destruction. Recognition occurs after dendritic cells present antigen, such as tumor antigen, to T cells, generating an adaptive response. Therefore, the potential of berries to aid cancer immune-therapies by, for example, regulating dendritic cells, warrants further investigation in animal and human studies. More information is also needed about berries’ effects on the entire spectrum of immunity so that a comprehensive view can inform efforts to use berries to enhance immune responses during cancer prevention and treatment. This review summarizes the effects of berries as anti-tumor agents from the immunological perspective in tumor-bearing animals and humans.
Berries contain abundant phytochemicals that have been shown to delay cancer development through multiple mechanisms such as altering gut microbiome and host metabolome, but understanding their ability to regulate cancer immunity is only beginning to be explored [1–10]. It is known, however, that phytochemicals can modulate the immune response by targeting key immune cells that control the pro- or anti-inflammatory microenvironment, thus helping to suppress tumor progression . Moreover, these compounds vary so greatly in structure and function that they can target a wide range of cancer cells, immune cells and their cytokines [12–26].
Berry is a simple indehiscent fruit (it does not split open to release its seeds when ripe), has a few or many seeds, and is derived from a single, simple, or compound ovary . Thus, berries include many commonly consumed fruits and vegetables, such as strawberries, blueberries, blackberries, red raspberries, black raspberries, cranberries, grape, kiwi, banana, tomatoes, eggplant, cucumber, watermelon, etc., as well as many uncommon types, such as gooseberries, Goji berries, elderberries, noni (Morinda citrifolia), and acai (Euterpe oleracea Mart.), etc. We used these terms and “cancer immunity” to search PubMed, and mainly focused on animal cancer models and human studies. Therefore, this review summarized the findings of berries as anti-tumor agents in an immunological perspective view.
Innate and adaptive immunity are the two immune responses. Innate immunity involves dendritic cells (DCs), macrophages, neutrophils, natural killer (NK) cells, granulocytes, basophils, eosinophils, and mast cells. Adaptive immunity involves predominantly T cells and B cells . Immune defense mechanisms also employ various soluble factors, such as chemokines, cytokines, and immunoglobulins. Both innate and adaptive immunity closely interact with each other. For example, antigen-presenting cells (such as DCs and macrophages) identify and “present” cancer cells to effector cells (such as T cells and B cells), which then destroy them. Recently, cancer immune-therapies have generated intense interest . DCs are an important target for generating specific anti-tumor immunity , as they trigger adaptive responses by presenting tumor antigens to T cells. T cells are categorized by cell membrane markers such as CD4 and CD8 . CD8+ T cells, which secrete interferon gamma (IFN-γ), have cytolytic activity against tumor cells . Interestingly, this cytolytic activity and the persistence of CD8+ T cells depend largely on the action of CD4+ T helper cells . Thus, one key to an optimal response against cancer is to establish a tumor-specific CD4+ T helper cell response .
NK cells spontaneously kill cells that are deemed to be dangerous to the host, such as cancer cells, and thus are presumed to be key effectors in cancer immune-surveillance . NK cells are usually defined as CD3–CD56+ in humans and CD3–NK1.1+ or CD3–NKp46+ in mice . In humans, these cells account for 5% –15% of circulating lymphocytes in the blood. Several mechanisms enable NK cells to distinguish healthy cells from target cells. These mechanisms integrate signals from different receptors and form the basis of NK cell activation . NK cells secret IFN-γ and they express inhibitory receptors of the major histocompatibility complex (MHC) class I . Binding of self MHC class I to the developing NK cells allow their “licensing” and the tolerance of NK cells . However, cells undergoing malignant transformation often lose their expression of MHC class I molecules, thereby escaping NK cells’ surveillance .
The complexity of the tumor microenvironment determines the outcome of immune cells, especially those with dual functions, such as macrophages and neutrophils . Tumor-associated macrophages derived from circulating monocytes are among the most abundant cells in the tumor microenvironment [33, 34]. Normally, they promote both innate and adaptive immunity and phagocytize dead or dying cells and cell debris . In the tumor microenvironment, however, tumors re-educate macrophages to promote tumor growth and spread . Thus, tumor-associated macrophages suppress adaptive immunity and enhance angiogenesis, tumor cell invasion, and intravasation into blood vessels . Also, different subsets of tumor-associated macrophages coexist in different tumor microenvironments . For example, M1-like, or classically activated, macrophages secret cytokines such as interleukin 6 (IL-6), IL-12, and tumor necrosis factor α (TNF-α), etc. They produce reactive oxygen species (ROS). Thus, M1-like macrophages are generally pro-inflammatory, pro-immunity, and anti-tumor . On the other hand, M2-like, or alternatively activated, macrophages secrete cytokines such as IL-10, IL-1β, transforming growth factor β (TGF-β), matrix metalloproteinase (MMPs), etc. Therefore, M2-like macrophages are predominately anti-inflammatory, immunosuppressive, pro-angiogenic, and pro-tumor . Neutrophils serve as a host’s first defense against invading microorganisms through their attraction to the primary site and their contribution to tissue repair . They can, however, infiltrate the tumor microenvironment to become tumor-associated immune-suppressive neutrophils and secret cytokines such as IL-1β, arginase-1, MMPs, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), etc [37, 38].
The immunomodulatory effects of berry compounds on cultured cells have been extensively summarized in other reviews [1, 39], and will not be repeated here. This review focuses on immunomodulation by phytochemicals found in berries, berry extracts, or whole berries as shown in tumor-bearing animal models (Table 1) and human studies (Table 2).
|Berries or berry components||Doses and Routes||Cancer types||Animal models||Immunological effects||Ref.|
|Black raspberries (BRBs)||6.1%, in the diet||Esophageal squamous cell carcinoma (ESCC)||N-nitrosomethylbenzylamine-induced ESCC in rats||IL-1β decreased||40|
|Anthocyanins (AC) from BRBs||3.8 mmol/g, in the diet||IL-10 and IL-12 increased|
|Protocatechuic acid (PCA)||500 ppm, in the diet||Macrophages and neutrophils decreased|
|BRBs||5%, in the diet||Colon cancer||ApcMin/+ mice||GR-1+ neutrophils and IL-1β increased in colonic lamina propria||41|
|GR-1+ neutrophils and IL-1β decreased in colon polyps|
|ApcMin/+ mice treated overnight with DSS||Tissue-infiltrating NK cells increased||42|
|Azoxymethane (AOM)-treated mice treated overnight with DSS|
|Red raspberry pulp polysaccharides||100, 200, 400 mg/kg daily×2 weeks, oral||Melanoma||Mouse B16F10 melanoma cells in C57BL/6 mice||TNF-α, IFN-γ, IL-2 increased||43|
|Laricitrin||30 mg/kg daily×3 days, i.p.||Lung cancer||Mouse Lewis lung carcinoma cells in C57BL/6 mice||IL-10 decreased in dendritic cells|
IL-12 increased in dendritic cells
IFN-γ increased in CD4+ T cells
IL-4 and IL-5 decreased in CD4+ T cells
|Grape seed proanthocyanidins||200 mg/kg daily×10 days, oral||Sarcoma||Mouse sarcoma S180 cells in BALB/c mice||NK cell cytotoxicity increased|
IL-2 and INF-γ increased
|Grape antioxidant dietary fiber from red grape pomace||1%, in the diet||Colon cancer||ApcMin/+ mice||Alteration of genes associated with the immune response||48|
|Resveratrol||10 mmol/mouse, topical||Skin cancer||Dimethylbenz(a)anthracene (DMBA)-induced skin cancer||IFN-γ and IL-12 levels increased||49|
|12.5, 25, 50 mg/kg daily×3 weeks, oral||Lymphocytic leukemia||Mouse L1210 lymphocytic leukemia in BALB/c mice||IL-6 decreased||50|
|CD4/CD8 ratio increased|
|4 mg/kg×1 dose, i.p.||Lymphoma||Mouse lymphoma EG7 cells in C57BL/6 mice||CD4+ CD25+ T regulatory cells decreased|
IFN-γ increased in CD8+ T cells
|Polysaccharide-rich substance (noni-ppt) from noni||0.5 mg/mouse×4-5 doses, i.p.||Sarcoma ascites tumor||Mouse sarcoma 180 cells in DBA/2, C57BL/6, and BALB/c mice||Requires functional macrophages, T cells and NK cells||53|
|Fermented noni exudate||500 mL/mouse daily×3 days. i.p.||Sarcoma||Mouse sarcoma 180 cells in C57BL/6, nude, and beige mice||Granulocytes and NK cells increased||54|
|Requires functional NK cells and lymphocytes|
|M. alba L. fruit extract (white mulberry)||100, 300 mg/kg, in the diet||Colon cancer||Mouse CT26 cells in BALB/c mice||NK cell activity, cytotoxic T lymphocyte activity, and IFN-γ increased||55|
|Berry fruits||Intake amount||Human populations||Immunological effects||Ref.|
|Black raspberries||60 g freeze-dried berries daily for 1–9 weeks||Colon cancer patients||The number and cytotoxicity of NK cells increased||42|
|Various fruits such as grape, strawberry, raspberry, currant, blueberry, apple, and cherry||Servings in questionnaire||General population||No overall association with the risk of lymphoma||59|
|Fruit juice, including apple juice, orange juice, grape juice, prune juice, and other juice||Servings in questionnaire||Nurses Health professionals||Lower EDIP scores||60|
|Prudent dietary pattern||High intakes of vegetables, fruits, whole grain products; low intakes of refined grain products||Healthy individuals||A protective effect against cancer initiation or development||61|
|A tomato-based drink (Lyc-o-Mato)||Lyc-o-Mato drink daily containing 5.7 mg of lycopene, 3.7 mg of phytoene, 2.7 mg of phytofluene, 1 mg of beta-carotene, and 1.8 mg of alpha-tocopherol for 26 days||Healthy individuals||TNF-α decreased||62|
|Tomato oleoresin extract capsules||Tomato oleoresin extract capsules daily containing 14.64 mg lycopene, 1.44 mg phytoene, 1.32 mg phytofluene, and 3.543 mg alpha-tocopherol for 2 weeks||Healthy individuals||IL-4 decreased in smokers||63|
|Blueberry-apple juice||One liter drink daily providing 97 mg quercetin and 16 mg ascorbic acid for 4 weeks||Healthy individuals||Alteration in many pathways||64|
3Studies of tumor-bearing animal models
Black raspberries (BRBs) are rich in anthocyanins (AC), which gut bacteria metabolize into protocatechuic acid (PCA). Our group investigated the ability of BRBs, BRB components (such as AC), and BRB metabolites (such as PCA) to inhibit N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer and to modulate immune cell trafficking in rats . All rats were injected with NMBA and then they were fed with either a control AIN-76A diet, or the control diet supplemented with either 6.1% of BRB powder (freeze-dried whole BRBs), an AC-rich fraction of BRBs (3.8μmol/g), or PCA (500 ppm) for 35 weeks. In comparison with the control diet, all three study diets (BRB powder, AC, and PCA) suppressed tumor development in the esophagus of the NMBA-treated rats. In addition, all three study diets increased the levels of IL-10 and IL-12 in the plasma. More importantly, all three diets also decreased infiltration of both macrophages and neutrophils into the esophagus. These results suggest that increased IL-12 expression could activate cytolytic NK and CD8+ T cells to kill tumor cells, while decreased infiltration of macrophages and neutrophils may reverse the immune-suppressing tumor microenvironment. However, the effect of higher IL-10 expression inside the tumor microenvironment warrants further investigation.
With regard to colon cancer, our group used ApcMin/+ mice as an animal model of colon cancer  and fed them with either a control AIN-76A diet or the control diet supplemented with 5% BRBs for 8 weeks. We observed that 5% BRBs suppressed colon polyp development in ApcMin/+ mice . The percentage of GR-1+ neutrophils and their cytokine secretion (IL-1β) were increased in colonic lamina propria, but decreased in colon polyps of ApcMin/+ mice by BRBs, suggesting that BRBs may reverse the immune-suppressing tumor microenvironment in the ApcMin/+ mice. In addition, the ability of BRBs to modulate NK cells was examined in two mouse models of colon cancer . We gave the ApcMin/+ mice and the azoxymethane (AOM)-injected mice 5% dextran sulfate sodium (DSS) in the drinking water overnight, in order to avoid the DSS-induced excessive inflammation that leads to colitis. This approach only slightly irritated the colon but still promoted colon carcinogenesis, with 100% incidence in both models. Four-week administration of 5% BRBs significantly suppressed colon cancer progression and increased the number of tissue-infiltrating NK cells, which might lead to their enhanced cytolytic killing of tumor cells.
Polysaccharides are a class of natural macromolecules. One group investigated the anti-tumor effects of red raspberry pulp polysaccharides (RPP) in a mouse model of melanoma . The yield of polysaccharide in the red raspberry pulp in Qinghai plateau is up to 12%, which provides a rich source for the extraction of polysaccharides. B16F10 mouse melanoma cells were implanted subcutaneously into C57BL/6 mice. These mice were given RPP orally at a dose of 100, 200, or 400 mg/kg of body weight for 2 weeks. RPP significantly inhibited the tumor growth with an inhibition ratio of 7.56%, 24.32% and 59.95%, respectively. In addition, RPP significantly increased the levels of TNF-α, IFN-γ, and IL-2 in the serum of the tumor-bearing mice in a dose-dependent manner. The increased secretion of TNF-α and IFN-γ might link to a stronger anti-tumor immune response by T cells and macrophages, which warrants further determination.
Laricitrin, a flavonoid found in grapes, was evaluated for its ability to modulate the immune system in mice bearing lung tumors . Lewis lung carcinoma (LLC) cells were implanted into male C57BL/6 mice via tail vein injection. The mice were intraperitoneally (i.p.) injected daily with either normal saline or laricitrin at a dose of 30 mg/kg of body weight, which was equivalent to the pharmacokinetics of grape phenols. Three doses of laricitrin decreased IL-10 levels and increased IL-12 levels in DCs from the tumors. IL-10 has shown to prevent the differentiation and maturation of DCs from monocytes, and impair the antigen-presenting function of DCs . Thus, the increased ratio of IL-12/IL-10 in the tumor microenvironment by laricitrin might enhance the tumor-destructive Th1 response of T cells against LLC cells. In addition, laricitrin increased IFN-γ levels, and decreased IL-4 and IL-5 levels in CD4+ T cells from the tumors, suggesting a switch from a Th2 response (IL-4 and IL-5 release) to a Th1 response (IFN-γ secretion) in CD4+ T cells by laricitrin treatment. These results indicate that laricitrin may suppress LLC tumor growth through stimulating the anti-tumor Th1 response of T cells.
Grape seeds are a rich source of proanthocyanidins, the major polyphenols in red wine . The abilities of grape seed proanthocyanidins to inhibit tumor growth and modulate immune system have been examined in mice bearing the mouse sarcoma 180 cells . Female BALB/c mice were inoculated subcutaneously with the sarcoma 180 cells. The mice were orally given either normal saline or grape seed proanthocyanidins at a dose of 200 mg/kg of body weight daily for 10 days. This study found that grape seed proanthocyanidins significantly suppressed the tumor growth, increased the cytotoxicity of NK cells, and stimulate their secretion of IL-2 and IFN-γ in splenic lymphocytes. More importantly, when combining grape seed proanthocyanidins with doxorubicin, an anthracycline antibiotic in cancer therapies, grape seed proanthocyanidins strongly enhanced the anti-tumor effects of doxorubicin through reversing the immune-suppressive side effects that were caused by doxorubicin. These results suggest a potential combination of immune-therapeutic regimen of grape seed proanthocyanidins and doxorubicin.
Dietary fiber is another rich source of proanthocyanidins. One group treated ApcMin/+ mice either a control diet (Teklad Global 18% Protein rodent diet), or the control diet supplemented with 1% grape antioxidant dietary fiber (GADF), a lyophilized red grape pomace containing proanthocyanidins-rich dietary fiber, for 6 weeks . This study found that GADF suppressed the intestinal tumor development, and downregulated several genes associated with the immune response, such as CXCR4 signaling, which has been reported to be involved in the tumorigenesis and lymph node metastasis.
Many studies have demonstrated the anti-tumor effects of resveratrol (trans-3,5,4-trihydroxystilbene), a polyphenol found in red grapes and in several other plant sources. One group pre-treated the C3H/He mice with 10 mmol/mouse resveratrol by applying it topically to the skin 1 hr prior to the exposure to dimethylbenz(a)anthracene (DMBA), a skin carcinogen . Resveratrol significantly suppressed DMBA-induced skin tumorigenesis and angiogenesis. In addition, resveratrol increased the IFN-γ and IL-12 levels in skin lysate, which may stimulate the generation of IFN-γ-producing Th1-cells. These effects caused by resveratrol treatment were dependent on the function of the toll-like receptor 4 (TLR4).
Another group investigated the anti-tumor effects of resveratrol against leukemia . Mouse lymphocytic leukemia cells L1210 were i.p. injected to male BALB/c mice, and then the mice were orally given either water or resveratrol daily at doses of 12.5, 25, and 50 mg/kg of body weight for 3 weeks. Resveratrol significantly prolonged the survival of these L1210-bearing mice in a dose-dependent manner. Interestingly, resveratrol significantly decreased the levels of intracellular IL-6 in a dose-dependent manner. Whether the lower IL-6 expression associated with a decreased macrophage population needs further investigation. In addition, resveratrol (25 and 50 mg/kg, but not 12.5 mg/kg) increased the CD4/CD8 ratios in the peripheral blood. However, the function of these T cells in the peripheral blood and whether they directly contributed to the tumor inhibition remain unclear.
In a mouse model of lymphoma, mouse lymphoma EG7 cells were inoculated subcutaneously (s.c.) into female C57BL/6 mice . Then these mice were given a single i.p. injection of either control or resveratrol at a dose of 4 mg/kg of body weight. Resveratrol decreased the percentage of CD4+ CD25+ T regulatory cells and levels of TGF-β in splenocytes, suggesting resveratrol could reverse the tumor-suppressing immune microenvironment. In addition, upon the treatment of resveratrol ex vivo to the cells from lymph nodes of the tumor-bearing mice, IFN-γ expression in CD8+ T cells was increased, suggesting an enhanced cytolytic function of CD8+ T cells against lymphoma cells.
Morinda citrifolia L. (noni) has been one of the most important traditional medicinal plants in Polynesia for more than 2000 years . A polysaccharide-rich substance from the juice of noni fruit (Noni-ppt at a dose of 0.5 mg/mouse, 4–5 doses) produced a significantly higher cure rate in mice bearing sarcoma 180 ascites tumors . Importantly, the observed anti-tumor activities of Noni-ppt were dependent on the function of macrophages, T cells, and NK cells, since administration of a specific inhibitor of each immune cell type could completely abolish the beneficial effects. In addition, the anti-tumor effects of Noni-ppt were also dependent on Th1 cytokine (IFN-γ), but not Th2 cytokines (IL-4 or IL-10). These results suggest an overall cytotoxicity-dominant immune status (Th1) was required for the protective effects of Noni-ppt against tumors.
Another group investigated the anti-tumor effects of fermented noni exudate (fNE) against sarcoma 180 tumors . Three-day treatment of 500μl/mouse/day fNE significantly increased the percentage of granulocytes and NK cells in the peripheral blood, peritoneum, and spleen. Importantly, NK cells play the most important role in fNE-produced anti-tumor effects, while functional lymphocytes partially contribute to the beneficial effects.
Morus alba L. (white mulberry), found in Asia, has been traditionally used in Korea . When orally given to BALB/c mice bearing CT26 colon tumors for 3 weeks, M. alba L. fruit extract (MFE) at a dose of 300 mg/kg of body weight, which was equivalent to 24.3 mg/kg human body weight, has been shown to significantly enhance the anti-tumor activity when in combination with 5-fluorouracil, and strongly promote NK cell activity, cytotoxic T lymphocyte activity, and IFN-γ production in spleen .
In summary, studies have examined potential abilities of modulating immune system in various animal models of cancer by berries and their phytochemicals. They have shown to promote the cytotoxicity of NK and CD8+ T cells, as well as to boost IFN-γ secretion. However, the effects of berries on other immune cells, such as macrophages and neutrophils, and their cytokine production, such as IL-10, have not been consistently reported across studies. This could be attributed to the dual functions of these immune cells. The context of tumor microenvironment could shape the outcome of these immune cells, which may lead to different effects upon berry treatment.
NK cells are an essential component of innate immunity against cancer development . Our group investigated the effects of BRBs on NK cells in a pre-surgical window of opportunity trial in colorectal cancer patients. Twenty colorectal cancer patients consumed 60 g/day freeze-dried BRB powder for 1–9 weeks. Then biopsies of colorectal adenocarcinomas were collected before and after BRB consumption . Using immunohistochemistry, we demonstrated a significantly increased number of tumor-infiltrating NK cells (CD56) and enhanced cytotoxicity of these NK cells (CD107a) after BRB intervention .
Since very few human studies have directly examined the effects of berries on cancer patients’ immune response, we also include some epidemiologic studies regarding cancer patients, as well as some berry-feeding studies involving healthy volunteers. One study determined the relationship between personalized dietary intervention and clinical measurements such as immune cell-mediated cytotoxicity in cancer patients . Cancer patients, including those with pancreatic cancer, bile duct cancer, lung cancer, breast cancer, colon cancer, hepatocellular carcinoma, glioblastoma, ovarian cancer, cecal cancer, and osteosarcoma, received either a treatment-support diet if they were undergoing chemotherapy (n = 10), or a remission-support diet if they were in remission (n = 10) for 21–61 days . Both diets were low glycemic, low fat, and high in plant protein. The treatment-support diet contained an additional 0.5 servings of protein. This study found an increased tendency in immune cell-mediated cytotoxicity in the treatment-support group. However, since regular meals, which contain garlic, onion, tomato, shiitake, rice bran, kale, blueberry, pineapples, and/or turmeric powder, were provided to all subjects, the potential effects of berries cannot be concluded.
Another study investigated the effects of diet on lymphomas, a heterogeneous group of malignant diseases of immune system cells . The European Prospective Investigation into Cancer and Nutrition (EPIC) trial identified 849 lymphoma cases among 411,097 participants during a median follow-up of 6.4 years. This trial estimated fruit consumption data from validated dietary questionnaires , which includes various fruits such as grape, strawberry, raspberry, currant, blueberry, apple, and cherry. However, no overall association between total fruit consumption and the risk of lymphoma was detected.
Dietary patterns might be linked to colorectal carcinogenesis. They could affect systemic and local intestinal inflammation, and chronic inflammation interferes with the adaptive immune response . Food frequency questionnaire (FFQ) data were collected from the databases of 2 prospective cohort studies: the Nurses’ Health Study (since 1976) and the Health Professionals Follow-Up Study (since 1986) . An empirical dietary inflammatory pattern (EDIP) score calculated based on FFQ data was used to correlate dietary patterns with colorectal carcinoma subtype. In particular, fruit juice, including apple juice, orange juice, grape juice, prune juice, and other juice, contributed to low EDIP scores. A higher EDIP score represented a pro-inflammatory dietary pattern. During the follow-up of 124,433 participants, 1,311 cases of colon and rectal cancer with available tissue data were documented. The association between the EDIP score and colorectal cancer risk was significant (ptrend = 0.02. Interestingly, the association varied based on the degree of peritumoral lymphocytic reaction (pheterogeneity < 0.001). A higher EDIP score associated with an increased risk of colorectal cancer when the peritumoral lymphocytic reaction was absent or at a low degree (ptrend < 0.001). However, when the peritumoral lymphocytic reaction was intermediate or high, there was no risk of tumors. These results suggest an important role of the host immune response.
One cross-section study examined the associations between dietary patterns and gene expression profiles of healthy men and women . Of 254 participants recruited from the greater Quebec City metropolitan area, 210 completed the study protocol. Dietary patterns were derived from a FFQ. RNA was extracted from peripheral blood mononuclear cells (PBMCs) from 30 fasting participants. The results identified two dietary patterns. The Prudent dietary pattern was characterized by high intakes of vegetables, fruits, and whole grain products, and low intakes of refined grain products. The Western dietary pattern was defined by high intakes of refined grain products, desserts, sweets, and processed meats. Both the dietary patterns induce gene changes in related with cancer, immune, and inflammation. Interestingly, the Prudent dietary pattern seems to have a protective effect against cancer initiation or development, while the Western dietary pattern has an opposite effect.
Consumption of tomatoes and their products at a regular basis has been shown to associate with a lower risk of several types of cancer . In a placebo-controlled, double-blind, crossover study, 26 healthy young volunteers (age < 30 years) drank either a tomato-based drink (Lyc-o-Mato) (containing 5.7 mg of lycopene, 3.7 mg of phytoene, 2.7 mg of phytofluene, 1 mg of beta-carotene, and 1.8 mg of alpha-tocopherol) or a placebo drink for 26 days . Meanwhile during the study, they maintained their original habitual diet. TNF-α levels in the whole blood were 34.4% lower in the subjects who drank Lyc-o-Mato. Another double-blinded, randomized, placebo-controlled study determined whether 2-week consumption of a tomato oleoresin extract affected immune functions of peripheral blood lymphocytes in healthy nonsmokers and smokers . Fifteen nonsmokers and 12 smokers were given three capsules of tomato oleoresin extract daily, with each capsule containing 4.88 mg lycopene, 0.48 mg phytoene, 0.44 mg phytofluene, and 1.181 mg alpha-tocopherol. Tomato oleoresin extract significantly reduced IL-4 production in smokers, similar to the level found in nonsmokers. These studies suggest a potential anti-inflammatory effect of tomato.
The concept of the exposome in a human nutrigenomics study involving in-depth analyses of gene expression responses was applied in a dietary intervention trial with blueberry-apple juice . For 4 weeks, 168 healthy volunteers consumed 1 liter of a custom-made blueberry-apple juice mixture every day, which provided 97 mg quercetin and 16 mg ascorbic acid. Blood collected before and after the intervention was used for plasma and lymphocyte analyses. The results showed that many pathways were altered in lymphocytes by the consumption of blueberry–apple juice. For example, in the NF-κB pathway, RELB, IKKβ and IKKγ were upregulated, whereas IKKα was downregulated. In the JAK/STAT pathway, JAK1 and STAT3 were downregulated, whereas JAK2, JAK3, STAT1, and STAT6 were upregulated. The juice also modulated genes involved in innate and adaptive immunity that are important for inducing anti-tumor immune responses.
In summary, berry intervention studies in humans involved fresh fruits and vegetables, juice, and freeze-dried powder. Encouragingly, our group demonstrated that BRBs increased the number and function of NK cells of colorectal cancer patients. However, very few studies directly examined the immune-modulating effects of berries on cancer patients. Although some large epidemiologic studies show that berry consumption might contribute to a lower risk of developing cancer, these studies usually categorize food items into several big groups, and berry is not an independent group. Therefore, the findings from epidemiologic studies have mixed results. Furthermore, berries could modulate genes involved in both innate and adaptive immunity in healthy individuals, which are important for inducing anti-tumor immune responses. We also need to consider that healthy volunteers can have very different immune system compared to that of cancer patients, so that any observations in healthy volunteers may not be able to translate into cancer patients. Therefore, much more clinical studies are needed to investigate the potential of berries and their components on the cancer immunity, as well as the mechanisms of their actions.
The literature shows some evidence that berries and their phytochemicals could modulate immunity to delay cancer development and progression. The wide range of phytochemicals in berries possibly explains the diversity of their effects on immune cells and cancer immunity. Recently, cancer immune-therapies, which depend on T cell recognition of tumor cells, have generated intense interest because of their success in treating some cancers . The potential of berries and their phytochemicals to aid cancer immune-therapies— by regulating DCs, for example— warrants investigation beyond laboratory studies. In addition, more effort is needed to investigate the effects of berries and their phytochemicals on the entire spectrum of cancer immunity to provide a comprehensive picture of how they could be used to modulate immunity during cancer prevention and treatment.
This work was partially supported by NIH grant 5 R01 CA148818 and American Cancer Society, RSG-13-138-01— CNE to L.-S. Wang. We apologize to the investigators whose work could not be cited due to space limitation.
Zheng YY , Viswanathan B , Kesarwani P , Mehrotra S. Dietary agents in cancer prevention: An immunological perspective. Photochem Photobiol. 2012;88(5):1083-98. doi: 10.1111/j.1751-1097.2012.01128.x
Pan P , Yu J , Wang LS. Colon Cancer: What We Eat. Surg Oncol Clin N Am. 2018;27(2):243-67. doi: 10.1016/j.soc.2017.11.002
Pan P , Huang YW , Oshima K , Yearsley M , Zhang J , Yu J , et al. Could Aspirin and Diets High in Fiber Act Synergistically to Reduce the Risk of Colon Cancer in Humans? Int J Mol Sci. 2018;19(1). doi: 10.3390/ijms19010166
Pan P , Lam V , Salzman N , Huang YW , Yu J , Zhang J , et al. Black Raspberries and Their Anthocyanin and Fiber Fractions Alter the Composition and Diversity of Gut Microbiota in F-344 Rats. Nutr Cancer. 2017:1-9. doi: 10.1080/01635581.2017.1340491
Pan P , Skaer CW , Wang HT , Kreiser MA , Stirdivant SM , Oshima K , et al. Systemic Metabolite Changes in Wild-type C57BL/6 Mice Fed Black Raspberries. Nutr Cancer. 2017;69(2):299-306. doi: 10.1080/01635581.2017.1263748
Pan P , Skaer CW , Wang HT , Stirdivant SM , Young MR , Oshima K , et al. Black raspberries suppress colonic adenoma development in ApcMin/+ mice: Relation to metabolite profiles. Carcinogenesis. 2015;36(10):1245-53. doi: 10.1093/carcin/bgv117
Pan P , Skaer CW , Stirdivant SM , Young MR , Stoner GD , Lechner JF , et al. Beneficial Regulation of Metabolic Profiles by Black Raspberries in Human Colorectal Cancer Patients. Cancer Prev Res (Phila). 2015;8(8):743-50. doi: 10.1158/1940-6207.CAPR-15-0065
Blumberg JB , Basu A , Krueger CG , Lila MA , Neto CC , Novotny JA , et al. Impact of Cranberries on Gut Microbiota and Cardiometabolic Health: Proceedings of the Cranberry Health Research Conference 2015. Adv Nutr. 2016;7(4):759S-70S. doi: 10.3945/an.116.012583
Morais CA , de Rosso VV , Estadella D , Pisani LP. Anthocyanins as inflammatory modulators and the role of the gut microbiota. The Journal of Nutritional Biochemistry. 2016;33:1-7. doi: 10.1016/j.jnutbio.2015.11.008
G Du , Piacente S , Pizza C , Montoro P. Metabolomics of Healthy Berry Fruits. Current Medicinal Chemistry. 2016.
Albini A , Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer. 2007;7(2):139-47. doi: 10.1038/nrc2067
Milani A , Basirnejad M , Shahbazi S , Bolhassani A. Carotenoids: Biochemistry, pharmacology and treatment. Br J Pharmacol. 2017;174(11):1290-324. doi: 10.1111/bph.13625
de la Lastra CA , Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications. Mol Nutr Food Res. 2005;49(5):405-30 doi: 10.1002/mnfr.200500022
Piotrowska H , Kucinska M , Murias M. Biological activity of piceatannol: Leaving the shadow of resveratrol. Mutat Res. 2012;750(1):60-82 doi: 10.1016/j.mrrev.2011.11.001
Yang X , Li X , Ren J. From French Paradox to cancer treatment: Anti-cancer activities and mechanisms of resveratrol. Anticancer Agents Med Chem. 2014;14(6):806-25.
Yang B , Liu P. Composition and biological activities of hydrolyzable tannins of fruits of Phyllanthus emblica. J Agric Food Chem. 2014;62(3):529-41. doi: 10.1021/jf404703k
Brown AC . Anticancer activity of Morinda citrifolia (Noni) fruit: A review. Phytother Res. 2012;26(10):1427-40. doi: 10.1002/ptr.4595
Giampieri F , Gasparrini M , Forbes-Hernandez TY , Mazzoni L , Capocasa F , Sabbadini S , et al. Overexpression of the Anthocyanidin Synthase Gene in Strawberry Enhances Antioxidant Capacity and Cytotoxic Effects on Human Hepatic Cancer Cells. J Agric Food Chem. 2018;66(3):581-92. doi: 10.1021/acs.jafc.7b04177
Afrin S , Gasparrini M , Forbes-Hernandez TY , Reboredo-Rodriguez P , Mezzetti B , Varela-Lopez A , et al. Promising Health Benefits of the Strawberry: A Focus on Clinical Studies. J Agric Food Chem. 2016;64(22):4435-49. doi: 10.1021/acs.jafc.6b00857
Mazzoni L , Perez-Lopez P , Giampieri F , Alvarez-Suarez JM , Gasparrini M , Forbes-Hernandez TY , et al. The genetic aspects of berries: From field to health. J Sci Food Agric. 2016;96(2):365-71. doi: 10.1002/jsfa.7216
Giampieri F , Forbes-Hernandez TY , Gasparrini M , Alvarez-Suarez JM , Afrin S , Bompadre S , et al. Strawberry as a health promoter: An evidence based review. Food Funct. 2015;6(5):1386-98. doi: 10.1039/c5fo00147a
Giampieri F , Alvarez-Suarez JM , Battino M. Strawberry and human health: Effects beyond antioxidant activity. J Agric Food Chem. 2014;62(18):3867-76. doi: 10.1021/jf405455n
Alvarez-Suarez JM , Giampieri F , Tulipani S , Casoli T , Di Stefano G , Gonzalez-Paramas AM , et al. One-month strawberry-rich anthocyanin supplementation ameliorates cardiovascular risk, oxidative stress markers and platelet activation in humans. The Journal of Nutritional Biochemistry. 2014;25(3):289-94. doi: 10.1016/j.jnutbio.2013.11.002
Cheng J , Zhou ZW , Sheng HP , He LJ , Fan XW , He ZX , et al. An evidence-based update on the pharmacological activities and possible molecular targets of Lycium barbarum polysaccharides. Drug Des Devel Ther. 2015;9:33-78. doi: 10.2147/DDDT.S72892
Giampieri F , Forbes-Hernandez TY , Gasparrini M , Afrin S , Cianciosi D , Reboredo-Rodriguez P , et al. The healthy effects of strawberry bioactive compounds on molecular pathways related to chronic diseases. Ann N Y Acad Sci. 2017;1398(1):62-71. doi: 10.1111/nyas.13373
Afrin S , Giampieri F , Gasparrini M , Forbes-Hernandez TY , Varela-Lopez A , Quiles JL , et al. Chemopreventive and Therapeutic Effects of Edible Berries: A Focus on Colon Cancer Prevention and Treatment. Molecules (Basel, Switzerland). 2016;21(2):169. doi: 10.3390/molecules21020169
Pan P , Skaer C , Yu J , Zhao H , Ren H , Oshima K , et al. Berries and other natural products in the pancreatic cancer chemoprevention in human clinical trials. J Berry Res. 2017;7(3):147-61. doi: 10.3233/JBR-170159
Bigley V , Cytlak U , Collin M. Human dendritic cell immunodeficiencies. Semin Cell Dev Biol. 2018. doi: 10.1016/j.semcdb.2018.02.020
Bryant CE , Sutherland S , Kong B , Papadimitrious MS , Hart DNJ. Dendritic cells as cancer therapeutics. Semin Cell Dev Biol. 2018. doi: 10.1016/j.semcdb.2018.02.015
Bou Nasser Eddine F , Ramia E , Tosi G , Forlani G , Accolla RS. Tumor Immunology meets…Immunology: Modified cancer cells as professional APC for priming naive tumor-specific CD4+ T cells. Oncoimmunology. 2017;6(11):e1356149. doi: 10.1080/2162402X.2017.1356149
Guillerey C , Huntington ND , Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 2016;17(9):1025-36. doi: 10.1038/ni.3518
Medina-Echeverz J , Aranda F , Berraondo P. Myeloid-derived cells are key targets of tumor immunotherapy. Oncoimmunology. 2014;3:e28398. doi: 10.4161/onci.28398
Noy R , Pollard JW. Tumor-associated macrophages: From mechanisms to therapy. Immunity. 2014;41(1):49-61. doi: 10.1016/j.immuni.2014.06.010
Brown JM , Recht L , Strober S. The Promise of Targeting Macrophages in Cancer Therapy. Clin Cancer Res. 2017;23(13):3241-50. doi: 10.1158/1078-0432.CCR-16-3122
Lewis CE , Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605-12. doi: 10.1158/0008-5472.CAN-05-4005
Qian BZ , Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39-51. doi: 10.1016/j.cell.2010.03.014
Houghton AM . The paradox of tumor-associated neutrophils: Fueling tumor growth with cytotoxic substances. Cell Cycle. 2010;9(9):1732-7. doi: 10.4161/cc.9.9.11297
Bosurgi L , Bernink JH , Delgado Cuevas V , Gagliani N , Joannas L , Schmid ET , et al. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proc Natl Acad Sci U S A. 2013;110(32):13091-6. doi: 10.1073/pnas.1302507110
del Corno M , Scazzocchio B , Masella R , Gessani S. Regulation of Dendritic Cell Function by Dietary Polyphenols. Crit Rev Food Sci Nutr. 2016;56(5):737-47. doi: 10.1080/10408398.2012.713046
Peiffer DS , Wang LS , Zimmerman NP , Ransom BW , Carmella SG , Kuo CT , et al. Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer. Cancer Immunol Res. 2016;4(1):72-82. doi: 10.1158/2326-6066.Cir-15-0091
Pan P , C WS , Wang HT , Oshima K , Huang YW , Yu J , et al. Loss of free fatty acid receptor 2 enhances colonic adenoma development and reduces the chemopreventive effects of black raspberries in ApcMin/+ mice. Carcinogenesis. 2017;38(1):86-93. doi: 10.1093/carcin/bgw122
Pan P , Kang S , Wang Y , Liu K , Oshima K , Huang Y-W , et al. Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer. Frontiers in Immunology. 2017;8(997). doi: 10.3389/fimmu.2017.00997
Yang YJ , Xu HM , Suo YR. Raspberry pulp polysaccharides inhibit tumor growth via immunopotentiation and enhance docetaxel chemotherapy against malignant melanoma in vivo. Food Funct. 2015;6(9):3022-34. doi: 10.1039/c5fo00389j
Chang WA , Hung JY , Jian SF , Lin YS , Wu CY , Hsu YL , et al. Laricitrin ameliorates lung cancer-mediated dendritic cell suppression by inhibiting signal transducer and activator of transcription 3. Oncotarget. 2016;7(51):85220-34. doi: 10.18632/oncotarget.13240
Pinzon-Charry A , Maxwell T , Lopez JA. Dendritic cell dysfunction in cancer: A mechanism for immunosuppression. Immunol Cell Biol. 2005;83(5):451-61. doi: 10.1111/j.1440-1711.2005.01371.x
Katiyar SK . Grape seed proanthocyanidines and skin cancer prevention: Inhibition of oxidative stress and protection of immune system. Mol Nutr Food Res. 2008;52(Suppl 1):S71-6. doi: 10.1002/mnfr.200700198
Zhang XY , Li WG , Wu YJ , Gao MT. Amelioration of doxorubicin-induced myocardial oxidative stress and immunosuppression by grape seed proanthocyanidins in tumour-bearing mice. J Pharm Pharmacol. 2005;57(8):1043-52. doi: 10.1211/0022357056523
Sanchez-Tena S , Lizarraga D , Miranda A , Vinardell MP , Garcia-Garcia F , Dopazo J , et al. Grape antioxidant dietary fiber inhibits intestinal polyposis in ApcMin/+ mice: Relation to cell cycle and immune response. Carcinogenesis. 2013;34(8):1881-8. doi: 10.1093/carcin/bgt140
Yusuf N , Nasti TH , Meleth S , Elmets CA. Resveratrol enhances cell-mediated immune response to DMBA through TLR4 and prevents DMBA induced cutaneous carcinogenesis. Mol Carcinog. 2009;48(8):713-23. doi: 10.1002/mc.20517
Li T , Fan GX , Wang W , Li T , Yuan YK. Resveratrol induces apoptosis, influences IL-6 and exerts immunomodulatory effect on mouse lymphocytic leukemia both in vitro and in vivo. Int Immunopharmacol. 2007;7(9):1221-31. doi: 10.1016/j.intimp.2007.05.008
Yang Y , Paik JH , Cho D , Cho JA , Kim CW. Resveratrol induces the suppression of tumor-derived CD4+CD25+ regulatory T cells. Int Immunopharmacol. 2008;8(4):542-7. doi: 10.1016/j.intimp.2007.12.006
McClatchey W . From Polynesian healers to health food stores: Changing perspectives of Morinda citrifolia (Rubiaceae). Integrative Cancer Therapies. 2002;1(2):110-20; discussion 20. doi: 10.1177/1534735402001002002
Furusawa E , Hirazumi A , Story S , Jensen J. Antitumour potential of a polysaccharide-rich substance from the fruit juice of Morinda citrifolia (Noni) on sarcoma 180 ascites tumour in mice. Phytother Res. 2003;17(10):1158-64. doi: 10.1002/ptr.1307
Li J , Stickel SL , Bouton-Verville H , Burgin KE , Yu X , Wong DK , et al. Fermented Noni exudate (fNE): A mediator between immune system and anti-tumor activity. Oncology Reports. 2008;20(6):1505-9. doi:
Chang BY , Kim SB , Lee MK , Park H , Kim SY. Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4. Int J Mol Sci. 2015;16(10):24139-58. doi: 10.3390/ijms161024139
Deng Y , Wang F , Hughes T , Yu J. FOXOs in cancer immunity: Knowns and unknowns. Semin Cancer Biol. 2018. doi: 10.1016/j.semcancer.2018.01.005
Wang LS , Arnold M , Huang YW , Sardo C , Seguin C , Martin E , et al. Modulation of genetic and epigenetic biomarkers of colorectal cancer in humans by black raspberries: A phase I pilot study. Clin Cancer Res. 2011;17(3):598-610. doi: 10.1158/1078-0432.Ccr-10-1260
Lee GY , Lee JJ , Lee SM. Antioxidant and Anticoagulant Status Were Improved by Personalized Dietary Intervention Based on Biochemical and Clinical Parameters in Cancer Patients. Nutr Cancer. 2015;67(7):1083-92. doi: 10.1080/01635581.2015.1073754
Rohrmann S , Becker N , Linseisen J , Nieters A , Rudiger T , Raaschou-Nielsen O , et al. Fruit and vegetable consumption and lymphoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control. 2007;18(5):537-49. doi: 10.1007/s10552-007-0125-z
Liu L , Nishihara R , Qian ZR , Tabung FK , Nevo D , Zhang X , et al. Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor. Gastroenterology. 2017;153(6):1517-30.e14. doi: 10.1053/j.gastro.2017.08.045
Bouchard-Mercier A , Paradis AM , Rudkowska I , Lemieux S , Couture P , Vohl MC. Associations between dietary patterns and gene expression profiles of healthy men and women: A cross-sectional study. Nutr J. 2013;12:24. doi: 10.1186/1475-2891-12-24
Riso P , Visioli F , Grande S , Guarnieri S , Gardana C , Simonetti P , et al. Effect of a tomato-based drink on markers of inflammation, immunomodulation, and oxidative stress. J Agric Food Chem. 2006;54(7):2563-6. doi: 10.1021/jf053033c
Briviba K , Kulling SE , Moseneder J , Watzl B , Rechkemmer G , Bub A. Effects of supplementing a low-carotenoid diet with a tomato extract for 2 weeks on endogenous levels of DNA single strand breaks and immune functions in healthy non-smokers and smokers. Carcinogenesis. 2004;25(12):2373-8. doi: 10.1093/carcin/bgh249
van Breda SG , Wilms LC , Gaj S , Jennen DG , Briede JJ , Kleinjans JC , et al. The exposome concept in a human nutrigenomics study: Evaluating the impact of exposure to a complex mixture of phytochemicals using transcriptomics signatures. Mutagenesis. 2015;30(6):723-31. doi: 10.1093/mutage/gev008