Over the past decade, research has increasingly focused on integrating immunotherapy with diet and supplementation in cancer therapy. This interest has persisted despite global health challenges, highlighting the importance of exploring how nutrition can enhance cancer treatment outcomes.
Understanding Cancer Immunotherapy
Cancer immunotherapy employs various strategies to stimulate the patient's immune system to fight cancer. These strategies can be broadly classified as follows:
- Monoclonal antibodies (mAbs): These antibodies are designed to specifically target cancer cells, stimulating the patient’s immune response. Examples include trastuzumab and rituximab, used in breast cancer and lymphoma treatment.
- Immune checkpoint inhibitors (ICIs): ICIs block immune checkpoint proteins that regulate T-cell activation, restoring proper T-cell function and improving the immune response against cancer cells. Notable ICIs include ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab.
- Antibody-drug conjugates (ADCs): ADCs combine monoclonal antibodies with cytotoxic drugs, delivering targeted precision and reducing systemic toxicity. Examples include ado-trastuzumab emtansine and brentuximab vedotin.
- Immune cytokines: These molecules, including IL-2, interferon-alpha (IFN-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF), modulate the tumor microenvironment and activate immune cells.
- Adoptive Cell Therapy (ACT): ACT involves extracting, modifying, and reintroducing immune cells to enhance the body’s natural immune response to cancer. CAR T-cell therapy, a subset of ACT, has shown significant success in hematological malignancies.
The Role of Diet in Immune Cell Functioning
Diet plays a crucial role in modulating immune cell function and influencing cancer development. Chronic inflammation, often influenced by diet, can contribute to cancer progression.
- Macrophage Polarization: Macrophages, key immune cells, have two activation programs: classical (M1) and alternative (M2). Classical activation leads to inflammatory responses, while alternative activation supports tissue repair. Fatty acid metabolism, cell membrane composition, and diet can influence macrophage polarization, potentially affecting inflammation and cardiovascular disease risk.
- Dietary Inflammatory Index (DII): The DII classifies foods based on their impact on inflammatory processes. Consuming foods with lower DII scores, such as fruits, vegetables, whole grains, lean proteins, healthy fats, and specific spices, can reduce systemic inflammation and mitigate cancer risk.
- Cytokine Production: The dietary composition of fatty acids influences cytokine production. Polyunsaturated fatty acids can hinder the production of Th1-type cytokines, which elicit proinflammatory responses. Maintaining a balance between Th1 and Th2 responses is crucial for cancers like hepatocellular carcinoma.
Dietary and Nutritional Strategies to Enhance Immunotherapy Effectiveness
Specific dietary and nutritional strategies can enhance the effectiveness of immunotherapy in melanoma treatment.
Fiber-Rich Foods and Gut Health
Consuming fibrous foods as prebiotics influences mucosal immune functions, reducing the risk of enteric inflammation. Undigested food can be converted into short-chain fatty acids (SCFAs), like butyrate, which alleviate inflammatory disorders by boosting T-regulatory cell (Treg) numbers and reducing IFN-γ levels.
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- Impact on Immune Cells: A fiber-rich diet proves beneficial when using ICIs, likely due to the increased SCFAs that stimulate immune cell differentiation and function.
- Gut Microbiome Modulation: In melanoma patients, higher dietary fiber intake has been associated with improved progression-free survival during ICB treatment.
- Clinical Evidence: Melanoma patients who ate high-fiber diets (more than 20 grams daily) and avoided probiotic supplements had the best responses to immunotherapy and lived the longest.
The Ketogenic Diet (KD)
The ketogenic diet (KD), characterized by high fat and low carbohydrate intake, has shown potential as an adjuvant in cancer immunotherapy.
- Metabolic Effects: KD lowers glucose levels, reducing lactate production by glycolytic cancer cells. Lactate serves as an inhibitor of dendritic cell maturation and hinders NK cell function, thereby limiting innate immunity effectors.
- Immune Cell Modulation: KD has been found to increase the CD4+ T-cell population and decrease Tregs. Additionally, Tregs from KD-fed animals produced less IL-10 when stimulated with tumor cells.
- ICI Responsiveness: KD may enhance ICI-based therapy effectiveness by modulating the expression of immune checkpoint molecules like CTLA-4 and PD-1 on tumor-infiltrating lymphocytes and PD-L1 on tumor cells.
- Clinical Studies: Studies on mice have shown enhanced responses to anti-PD-1 therapy when fed a KD, suggesting it may amplify the anticancer effects of PD-1 blockade.
High-Fat Diets (HFD)
While some anticancer immunotherapies benefit from very low carb or ketogenic diets, high-fat diets may worsen therapy outcomes.
- Proinflammatory Cytokines: HFD has been shown to increase cytokine production, including TNF-α, IL-1, and IL-6, in adipocyte cultures.
- Tumor Growth: HFD and HFD-induced obesity have been shown to accelerate tumor growth.
- Lipid Accumulation: The accumulation of lipid droplets has been positively linked to the advancement of various cancers, including melanoma and pancreatic cancer.
The Role of Probiotics
Research indicates that taking over-the-counter probiotic supplements was linked to worse survival and a poorer response to immunotherapy in some studies. Probiotics may lower the number of cancer-killing T-cells found in tumors, which are immune cells that help fight cancer.
Importance of a Balanced Diet
A balanced diet that incorporates fruits, vegetables, whole grains, lean proteins, and healthy fats is crucial for reducing systemic inflammation and supporting immune function.
Recent Research and Clinical Trials
Recent advancements, including single-cell sequencing, high-dimensional cytometry, and CRISPR‒Cas9 gene editing, have revolutionized immunology research, allowing in-depth exploration of immune cell heterogeneity and function.
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- DIET Trial: The DIET trial (NCT04645680) is a controlled feeding study designed to assess the role of diet in modulating the gut microbiome in the context of ICB in patients with melanoma.
- Raman Spectroscopy: Raman imaging, a label-free and noninvasive technique, is a potent approach for analyzing dietary-induced biochemical and morphological changes in immune cells.
Practical Recommendations for Patients on Immunotherapy
Patients undergoing immunotherapy for melanoma can consider the following dietary recommendations:
- Increase Fiber Intake: Aim for at least 20 grams of fiber daily through fruits, vegetables, legumes, and whole grains.
- Limit Processed Foods: Reduce the intake of processed foods, added sugars, and unhealthy fats.
- Avoid Probiotic Supplements: Exercise caution with over-the-counter probiotic supplements, as they may negatively impact immunotherapy response.
- Consult a Dietitian: Work with a registered dietitian for personalized advice tailored to individual needs and treatment plans.
- Manage Stress: Incorporate stress management techniques such as meditation, yoga, or other relaxation practices.
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