The Role of Micronutrient Supplementation in Enhancing Immune Function and Mitigating Immune-Related Adverse Events in Patients with Cancer Therapy: A Comprehensive Review
Keywords:
Micronutrient supplementation, Immunotherapy, Autoimmune diseases, Vitamin C, Vitamin DAbstract
Background: The role of micronutrient supplementation in enhancing immune function and mitigating adverse effects associated with cancer therapies has garnered increasing attention, particularly in the context of autoimmune diseases. Micronutrients such as vitamins and minerals are essential for maintaining optimal immune responses, yet their significance in oncological care is often underestimated.
Methods: This review synthesizes current literature on the impact of micronutrient supplementation, particularly vitamin C, vitamin D, and zinc, on immune modulation during cancer immunotherapy. A systematic assessment of epidemiological, clinical, and experimental studies was conducted to evaluate the efficacy of these micronutrients in improving patient outcomes, reducing immune-related adverse events, and enhancing the effectiveness of immunotherapy.
Results: The findings indicate that adequate micronutrient levels significantly contribute to immune competence, with deficiencies correlating to increased susceptibility to autoimmune disorders and adverse effects from immunotherapy. High-dose vitamin C has shown potential in augmenting T cell activity and reducing inflammation, while vitamin D supplementation has been associated with decreased incidence of autoimmune complications. Additionally, zinc has been recognized for its role in regulating immune responses and mitigating chemotherapy-related toxicities.
Conclusion: The incorporation of micronutrient supplementation into cancer treatment protocols may enhance therapeutic efficacy, reduce immune-related adverse events, and improve overall patient quality of life. Future research should focus on establishing definitive guidelines for micronutrient dosages and their interactions with conventional therapies to optimize clinical outcomes for cancer patients.
References
1. Klenner FR. Massive doses of vitamin C and the virus diseases. South Med Surg. 1951;113:101–107.
2. Mousavi S, Bereswill S, Heimesaat MM. Immunomodulatory and Antimicrobial Effects of Vitamin C. Eur J Microbiol Immunol (Bp) 2019;9:73–79.
3. Kumar NB, Hopkins K, Allen K, Riccardi D, Besterman-Dahan K, Moyers S. Use of complementary/integrative nutritional therapies during cancer treatment: implications in clinical practice. Cancer Control. 2002;9:236–243.
4. Kartolo A, Sattar J, Sahai V, Baetz T, Lakoff JM. Predictors of immunotherapy-induced immune-related adverse events. Curr Oncol. 2018;25:e403–e410.
5. Tsao SY. The role of metronomic chemotherapy in the era of cancer immunotherapy: an oncologist's perspective. Curr Oncol. 2019;26:e422–e424.
6. Anderson R, Rapoport BL. Immune Dysregulation in Cancer Patients Undergoing Immune Checkpoint Inhibitor Treatment and Potential Predictive Strategies for Future Clinical Practice. Front Oncol. 2018;8:80.
7. Weinmann SC, Pisetsky DS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology (Oxford) 2019;58:vii59–vii67.
8. White-Gibson A, Lennon P, O'Regan E, Timon C. More than meets the eye. BMJ Case Rep. 2019;12
9. Spiers L, Coupe N, Payne M. Toxicities associated with checkpoint inhibitors-an overview. Rheumatology (Oxford) 2019;58:vii7–vii16.
10. Milling L, Zhang Y, Irvine DJ. Delivering safer immunotherapies for cancer. Adv Drug Deliv Rev. 2017;114:79–101.
11. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, Lenihan D, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.
12. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, Hallmeyer S, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–1768.
13. Maggini S, Pierre A, Calder PC. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients. 2018;10
14. Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017;9
15. Gombart AF, Pierre A, Maggini S. A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection. Nutrients. 2020;12
16. Prasad KN, Kumar A, Kochupillai V, Cole WC. High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. J Am Coll Nutr. 1999;18:13–25.
17. Name JJ, Souza ACR, Vasconcelos AR, Prado PS, Pereira CPM. Zinc, Vitamin D and Vitamin C: Perspectives for COVID-19 With a Focus on Physical Tissue Barrier Integrity. Front Nutr. 2020;7:606398.
18. Maggini S, Maldonado P, Cardim P, Newball CF, Sota Latino ER. Vitamins C, D and Zinc: Synergistic Roles in Immune Function and Infections. Vitam Miner. 2017;6:1–10.
19. Gorji A, Khaleghi Ghadiri M. Potential roles of micronutrient deficiency and immune system dysfunction in the coronavirus disease 2019 (COVID-19) pandemic. Nutrition. 2021;82:111047.
20. Bailey RL, West KP Jr, Black RE. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015;66 Suppl 2:22–33.
21. Katona P, Katona-Apte J. The interaction between nutrition and infection. Clin Infect Dis. 2008;46:1582–1588.
22. Pecora F, Persico F, Argentiero A, Neglia C, Esposito S. The Role of Micronutrients in Support of the Immune Response against Viral Infections. Nutrients. 2020;12
23. Abioye AI, Bromage S, Fawzi W. Effect of micronutrient supplements on influenza and other respiratory tract infections among adults: a systematic review and meta-analysis. BMJ Glob Health. 2021;6
24. Willett WC. Micronutrients and cancer risk. Am J Clin Nutr. 1994;59:1162S–1165S.
25. Cuenca-Micó O, Aceves C. Micronutrients and Breast Cancer Progression: A Systematic Review. Nutrients. 2020;12
26. Srivastava S, Dubey AK, Madaan R, Bala R, Gupta Y, Dhiman BS, Kumar S. Emergence of nutrigenomics and dietary components as a complementary therapy in cancer prevention. Environmental Science and Pollution Research. 2022 Dec;29(60):89853-73.
27. Mokbel K, Mokbel K. Chemoprevention of Breast Cancer With Vitamins and Micronutrients: A Concise Review. In Vivo. 2019;33:983–997.
28. M Waheed R, Aleksandra N, Matthias R. Scientific Evaluation of Dietary Factors in Cancer. J Nutr Med Diet Care. 2018;4:1–32.
29. Alam W, Ullah H, Santarcangelo C, Di Minno A, Khan H, Daglia M, Arciola CR. Micronutrient food supplements in patients with gastro-intestinal and hepatic cancers. International Journal of Molecular Sciences. 2021 Jul 27;22(15):8014.
30. Ambrosone CB, Zirpoli GR, Hutson AD, McCann WE, McCann SE, Barlow WE, Kelly KM, Cannioto R, Sucheston-Campbell LE, et al.. Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221) J Clin Oncol. 2020;38:804–814.
31. Yuen RC, Tsao SY. Embracing cancer immunotherapy with vital micronutrients. World Journal of Clinical Oncology. 2021 Sep 9;12(9):712.
32. Lopes NB, Almeida IV, Lucchetta L, Düsman E, Vicentini VE. Cytotoxicity of iodine-131 radiopharmaceutical in tumor and non-tumor human cells and radioprotection by integral juices of Vitis labrusca L. Brazilian Journal of Biology. 2022 Aug 22;82:e253206.
33. Yasueda A, Urushima H, Ito T. Efficacy and Interaction of Antioxidant Supplements as Adjuvant Therapy in Cancer Treatment: A Systematic Review. Integr Cancer Ther. 2016;15:17–39.
34. Prasad KN. Antioxidants in cancer care: when and how to use them as an adjunct to standard and experimental therapies. Expert Rev Anticancer Ther. 2003;3:903–915.
35. Singh K, Bhori M, Kasu YA, Bhat G, Marar T. Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity - Exploring the armoury of obscurity. Saudi Pharm J. 2018;26:177–190.
36. Simone CB 2nd, Simone NL, Simone V, Simone CB. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern Ther Health Med. 2007;13:22–28.
37. Sun Z, Zhu Y, Wang PP, Roebothan B, Zhao J, Dicks E, Cotterchio M, Buehler S, Campbell PT, McLaughlin JR, Parfrey PS. Reported intake of selected micronutrients and risk of colorectal cancer: results from a large population-based case-control study in Newfoundland, Labrador and Ontario, Canada. Anticancer Res. 2012;32:687–696.
38. Comito G, Ippolito L, Chiarugi P, Cirri P. Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness. Front Oncol. 2020;10:396.
39. Zhang J, Shi Z, Xu X, Yu Z, Mi J. The influence of microenvironment on tumor immunotherapy. FEBS J. 2019;286:4160–4175.
40. Muir A, Vander Heiden MG. The nutrient environment affects therapy. Science. 2018;360:962–963.
41. van Gorkom GNY, Klein Wolterink RGJ, Van Elssen CHMJ, Wieten L, Germeraad WTV, Bos GMJ. Influence of Vitamin C on Lymphocytes: An Overview. Antioxidants (Basel) 2018;7
42. Ang A, Pullar JM, Currie MJ, Vissers MCM. Vitamin C and immune cell function in inflammation and cancer. Biochem Soc Trans. 2018;46:1147–1159.
43. Mohammed BM, Fisher BJ, Kraskauskas D, Farkas D, Brophy DF, Fowler AA 3rd, Natarajan R. Vitamin C: a novel regulator of neutrophil extracellular trap formation. Nutrients. 2013;5:3131–3151.
44. Magrì A, Germano G, Lorenzato A, Lamba S, Chilà R, Montone M, Amodio V, Ceruti T, Sassi F, Arena S, Abrignani S, D'Incalci M, Zucchetti M, Di Nicolantonio F, Bardelli A. High-dose vitamin C enhances cancer immunotherapy. Sci Transl Med. 2020;12
45. Wu X, Hu W, Lu L, Zhao Y, Zhou Y, Xiao Z, Zhang L, Zhang H, Li X, Li W, Wang S, Cho CH, Shen J, Li M. Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment. Acta Pharm Sin B. 2019;9:203–219.
46. Chakraborti CK. Vitamin D as a promising anticancer agent. Indian J Pharmacol. 2011;43:113–120.
47. Hibberd MC, Wu M, Rodionov DA, Li X, Cheng J, Griffin NW, Barratt MJ, Giannone RJ, Hettich RL, Osterman AL, Gordon JI. The effects of micronutrient deficiencies on bacterial species from the human gut microbiota. Sci Transl Med. 2017;9
48. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–1089.
49. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–108.
50. Russo E, Nannini G, Dinu M, Pagliai G, Sofi F, Amedei A. Exploring the food-gut axis in immunotherapy response of cancer patients. World J Gastroenterol. 2020;26:4919–4932.
51. Shui L, Yang X, Li J, Yi C, Sun Q, Zhu H. Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy. Front Immunol. 2019;10:2989.
52. Tabatabaeizadeh SA, Tafazoli N, Ferns GA, Avan A, Ghayour-Mobarhan M. Vitamin D, the gut microbiome and inflammatory bowel disease. J Res Med Sci. 2018;23:75.
53. Singh P, Rawat A, Alwakeel M, Sharif E, Al Khodor S. The potential role of vitamin D supplementation as a gut microbiota modifier in healthy individuals. Sci Rep. 2020;10:21641.
54. Ciernikova S, Novisedlakova M, Cholujova D, Stevurkova V, Mego M. The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma. Biomedicines. 2020;8
55. Gröber U, Holzhauer P, Kisters K, Holick MF, Adamietz IA. Micronutrients in Oncological Intervention. Nutrients. 2016;8:163.
56. Jatoi A, Williams B, Nichols F, Marks R, Aubry MC, Wampfler J, Finke EE, Yang P. Is voluntary vitamin and mineral supplementation associated with better outcome in non-small cell lung cancer patients? Lung Cancer. 2005;49:77–84.
57. Wang F, Li R. Cancer Immunotherapy and Immunonutrition. MOJ Anat Physiol. 2017;3:146–147.
58. Luchtel RA, Bhagat T, Pradhan K, Jacobs WR Jr, Levine M, Verma A, Shenoy N. High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model. Proc Natl Acad Sci USA. 2020;117:1666–1677.
59. Raymond YC, Glenda CS, Meng LK. Effects of High Doses of Vitamin C on Cancer Patients in Singapore: Nine Cases. Integr Cancer Ther. 2016;15:197–204.
60. Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70:86–104.
61. Wessels I, Rink L. Micronutrients in autoimmune diseases: possible therapeutic benefits of zinc and vitamin D. J Nutr Biochem. 2020;77:108240.
62. Ströhle A, Wolters M, Hahn A. Micronutrients at the interface between inflammation and infection--ascorbic acid and calciferol. Part 2: calciferol and the significance of nutrient supplements. Inflamm Allergy Drug Targets. 2011;10:64–74.
63. Ginanjar E, Sumariyono , Setiati S, Setiyohadi B. Vitamin D and autoimmune disease. Acta Med Indones. 2007;39:133–141.
64. Pandolfi F, Franza L, Mandolini C, Conti P. Immune Modulation by Vitamin D: Special Emphasis on Its Role in Prevention and Treatment of Cancer. Clin Ther. 2017;39:884–893.
65. Todorova TT, Ermenlieva N, Tsankova G. Vitamin B12: Could It Be a Promising Immunotherapy? In: Metodiev K, editor. Immunotherapy - Myths, Reality, Ideas, Future, 2017: 85-100.
66. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–2644.
67. Wagner SC, Markosian B, Ajili N, Dolan BR, Kim AJ, Alexandrescu DT, Dasanu CA, Minev B, Koropatnick J, Marincola FM, Riordan NH. Intravenous ascorbic acid as an adjuvant to interleukin-2 immunotherapy. J Transl Med. 2014;12:127.
68. Mikirova N, Riordan N, Casciari J. Modulation of Cytokines in Cancer Patients by Intravenous Ascorbate Therapy. Med Sci Monit. 2016;22:14–25.
69. Karagün E, Ergin C, Baysak S, Erden G, Aktaş H, Ekiz Ö. The role of serum vitamin D levels in vitiligo. Postepy Dermatol Alergol. 2016;33:300–302.
70. AlGhamdi K, Kumar A, Moussa N. The role of vitamin D in melanogenesis with an emphasis on vitiligo. Indian J Dermatol Venereol Leprol. 2013;79:750–758.
71. Ma J, Wu D, Li C, Fan C, Chao N, Liu J, Li Y, Wang R, Miao W, Guan H, Shan Z, Teng W. Lower Serum 25-Hydroxyvitamin D Level is Associated With 3 Types of Autoimmune Thyroid Diseases. Medicine (Baltimore) 2015;94:e1639.
72. Holland DB, Wood EJ, Roberts SG, West MR, Cunliffe WJ. Epidermal keratin levels during oral 1-alpha-hydroxyvitamin D3 treatment for psoriasis. Skin Pharmacol. 1989;2:68–76.
73. Finamor DC, Sinigaglia-Coimbra R, Neves LC, Gutierrez M, Silva JJ, Torres LD, Surano F, Neto DJ, Novo NF, Juliano Y, Lopes AC, Coimbra CG. A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Dermatoendocrinol. 2013;5:222–234.
74. Failla CM, Carbone ML, Fortes C, Pagnanelli G, D'Atri S. Melanoma and Vitiligo: In Good Company. Int J Mol Sci. 2019;20
75. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol. 2018;19:345–361.
76. Weinbaum S, Ganatos P, Pfeffer R, Wen GB, Lee M, Chien S. On the time-dependent diffusion of macromolecules through transient open junctions and their subendothelial spread. I. Short-time model for cleft exit region. J Theor Biol. 1988;135:1–30.
77. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–952.
78. Derakhshandi H, Etemadifar M, Feizi A, Abtahi SH, Minagar A, Abtahi MA, Abtahi ZA, Dehghani A, Sajjadi S, Tabrizi N. Preventive effect of vitamin D3 supplementation on conversion of optic neuritis to clinically definite multiple sclerosis: a double blind, randomized, placebo-controlled pilot clinical trial. Acta Neurol Belg. 2013;113:257–263.
79. Simkin PA. Oral zinc sulphate in rheumatoid arthritis. Lancet. 1976;2:539–542.
80. Shidfar F, Aghasi M, Vafa M, Heydari I, Hosseini S, Shidfar S. Effects of combination of zinc and vitamin A supplementation on serum fasting blood sugar, insulin, apoprotein B and apoprotein A-I in patients with type I diabetes. Int J Food Sci Nutr. 2010;61:182–191.
81. Ataie-Jafari A, Loke SC, Rahmat AB, Larijani B, Abbasi F, Leow MK, Yassin Z. A randomized placebo-controlled trial of alphacalcidol on the preservation of beta cell function in children with recent onset type 1 diabetes. Clin Nutr. 2013;32:911–917.
82. Gabbay MA, Sato MN, Finazzo C, Duarte AJ, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β-cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med. 2012;166:601–607.
83. Treiber G, Prietl B, Fröhlich-Reiterer E, Lechner E, Ribitsch A, Fritsch M, Rami-Merhar B, Steigleder-Schweiger C, Graninger W, Borkenstein M, Pieber TR. Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - A randomized clinical trial. Clin Immunol. 2015;161:217–224.
84. Sadeghian G, Ziaei H, Nilforoushzadeh MA. Treatment of localized psoriasis with a topical formulation of zinc pyrithione. Acta Dermatovenerol Alp Pannonica Adriat. 2011;20:187–190.
85. Lima GL, Paupitz J, Aikawa NE, Takayama L, Bonfa E, Pereira RM. Vitamin D Supplementation in Adolescents and Young Adults With Juvenile Systemic Lupus Erythematosus for Improvement in Disease Activity and Fatigue Scores: A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Care Res (Hoboken) 2016;68:91–98.
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
CC Attribution 4.0
