Combining immunotherapy and natural immune stimulants: mechanisms and clinical implications

  • Khara LuciusEmail author
  • Jacob Hill
Letter to the Editors

Dear Editor,

The development of immunotherapy (IT) represents one of the most promising advances in oncology in the past several years. Indications for IT have expanded rapidly, and a growing number of patients with an increased variety of cancer diagnoses are being treated with these agents. At the same time, the use of complementary and integrative therapies among cancer patients is widespread (Tara et al. 2018), and many patients do not disclose or discuss these therapies with their physicians (Richardson et al. 2000). Patient use of nutritional supplements may include items that are considered natural immune stimulants (NIS). Our understanding of how NIS use may affect people who are being treated with IT is in its infancy. To the author’s knowledge, there are no clinical trials, and extremely limited preclinical data, examining the effect of combining IT and NIS. It is critical to consider the shared mechanisms of IT and NIS and how this combination may affect patients. We offer...



The Research Fellowship in Complementary and Integrative Health (5T32AT003378-12) from the National Center for Complementary and Integrative Health provides salary support for Dr. Hill.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to disclose regarding this review.


  1. Blandizzi C, Gionchetti P, Armuzzi A et al (2014) The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases. Int J Immunopathol Pharmacol 27:1–10. CrossRefGoogle Scholar
  2. Boutsikou E, Domvri K, Hardavella G et al (2018) Tumour necrosis factor, interferon-gamma and interleukins as predictive markers of antiprogrammed cell-death protein-1 treatment in advanced non-small cell lung cancer: a pragmatic approach in clinical practice. Ther Adv Med Oncol 10:1758835918768238. CrossRefGoogle Scholar
  3. Brucklacher-Waldert V, Stuerner K, Kolster M et al (2009) Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 132:3329–3341. CrossRefGoogle Scholar
  4. Cai X, Xu Y, Lin X (2006) Effects of radix Astragali injection on apoptosis of lymphocytes and immune function in patients with systemic lupus erythematosus. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi Chin J Integr Tradit West Med 26:443–445Google Scholar
  5. Callahan MK, Yang A, Tandon S et al (2011) Evaluation of serum IL-17 levels during ipilimumab therapy: correlation with colitis. ASCO Meet Abstr 29:2505Google Scholar
  6. Das R, Bar N, Ferreira M et al (2018) Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Investig 128:715–720. CrossRefGoogle Scholar
  7. Dong J, Gu H, Ma C et al (2005) Effects of large dose of Astragalus membranaceus on the dendritic cell induction of peripheral mononuclear cell and antigen presenting ability of dendritic cells in children with acute leukemia. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi Chin J Integr Tradit West Med 25:872–875Google Scholar
  8. Du X, Zhao B, Li J et al (2012) Astragalus polysaccharides enhance immune responses of HBV DNA vaccination via promoting the dendritic cell maturation and suppressing Treg frequency in mice. Int Immunopharmacol 14:463–470. CrossRefGoogle Scholar
  9. Dulos J, Carven GJ, van Boxtel SJ et al (2012) PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J Immunother 35(2):169–178. CrossRefGoogle Scholar
  10. Hansson I, Holmdahl R, Mattsson R (1990) Constant darkness enhances autoimmunity to type II collagen and exaggerates development of collagen-induced arthritis in DBA/1 mice. J Neuroimmunol 27:79–84. CrossRefGoogle Scholar
  11. Hou Y-C, Wu J-M, Wang M-Y et al (2015) Modulatory effects of Astragalus polysaccharides on T-cell polarization in mice with polymicrobial sepsis. Mediators Inflamm 2015:1–10. CrossRefGoogle Scholar
  12. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. CrossRefGoogle Scholar
  13. Kuklina EM (2014) Melatonin as potential inducer of Th17 cell differentiation. Med Hypotheses 83:404–406. CrossRefGoogle Scholar
  14. Li D, Cai W, Gu R et al (2013) Th17 cell plays a role in the pathogenesis of Hashimoto’s thyroiditis in patients. Clin Immunol 149:411–420. CrossRefGoogle Scholar
  15. Maruyama S, Akasaka T, Yamada K, Tachibana H (2009) Protein-bound polysaccharide-K (PSK) directly enhanced IgM production in the human B cell line BALL-1. Biomed Pharmacother 63:409–412. CrossRefGoogle Scholar
  16. Matsumura N, Ohtsuka M, Kikuchi N, Yamamoto T (2016) Exacerbation of psoriasis during nivolumab therapy for metastatic melanoma. Acta Derm Venereol 96:259–260. CrossRefGoogle Scholar
  17. Mattsson R, Hannsson I, Holmdahl R (1994) Pineal gland in autoimmunity: melatonin-dependent exaggeration of collagen-induced arthritis in mice. Autoimmunity 17:83–86CrossRefGoogle Scholar
  18. Olsen T, Rismo R, Cui G et al (2011) TH1 and TH17 interactions in untreated inflamed mucosa of inflammatory bowel disease, and their potential to mediate the inflammation. Cytokine 56:633–640. CrossRefGoogle Scholar
  19. Pedrinaci S, Algarra I, Garrido F (1999) Protein-bound polysaccharide (PSK) induces cytotoxic activity in the NKL human natural killer cell line. Int J Clin Lab Res 29:135–140CrossRefGoogle Scholar
  20. Pioli C, Caroleo MC, Nistico G, Doria G (1993) Melatonin increases antigen presentation and amplifies specific and non specific signals for T-cell proliferation. Int J Immunopharmacol 15:463–468CrossRefGoogle Scholar
  21. Postow MA, Chesney J, Pavlick AC et al (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006–2017. CrossRefGoogle Scholar
  22. Richardson MA, Sanders T, Palmer JL et al (2000) Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol 18:2505–2514. CrossRefGoogle Scholar
  23. Shao B-M, Xu W, Dai H et al (2004) A study on the immune receptors for polysaccharides from the roots of Astragalus membranaceus, a Chinese medicinal herb. Biochem Biophys Res Commun 320:1103–1111. CrossRefGoogle Scholar
  24. Tara A, Berman, Christina M, Annunziata AB (2018) Oncology patient and practitioner experience with complementary/alternative medicine at the NIH Clinical Center. In: 2018 ASCO annual meeting abstracts. Oncology patient and practitioner experience with complementary/alternative medicine at the NIH Clinical CenterGoogle Scholar
  25. Vetvicka V, Vetvickova J (2014) Natural immunomodulators and their stimulation of immune reaction: true or false? Anticancer Res 34:2275–2282Google Scholar
  26. Wang Y, Jin B, Ai F et al (2012) The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol 69:1213–1220. CrossRefGoogle Scholar
  27. Wang J, Dong B, Tan Y et al (2013) A study on the immunomodulation of polysaccharopeptide through the TLR4-TIRAP/MAL-MyD88 signaling pathway in PBMCs from breast cancer patients. Immunopharmacol Immunotoxicol 35:497–504. CrossRefGoogle Scholar
  28. Wolchok JD, Kluger H, Callahan MK et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133. CrossRefGoogle Scholar
  29. Yang S-P, Dong H, Wu Y-C (2008) Clinical effect of milkvetch extract oral liquid in preventing and treating children’s recurrent respiratory tract infection. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi Chin J Integr Tradit West Med 28:544–547Google Scholar
  30. Yang Y, Inatsuka C, Gad E et al (2014) Protein-bound polysaccharide-K induces IL-1β via TLR2 and NLRP3 inflammasome activation. Innate Immun 20:857–866. CrossRefGoogle Scholar
  31. Zhao XZ (1992) Effects of Astragalus membranaceus and Tripterygium hypoglancum on natural killer cell activity of peripheral blood mononuclear in systemic lupus erythematosus. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi Chin J Integr Tradit West Med 12:669–671, 645Google Scholar
  32. Zizzo G, De Santis M, Bosello SL et al (2011) Synovial fluid-derived T helper 17 cells correlate with inflammatory activity in arthritis, irrespectively of diagnosis. Clin Immunol 138:107–116. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for Integrative MedicineUniversity of Pittsburgh Medical CenterPittsburghUSA
  2. 2.Program on Integrative Medicine, Department of Physical Medicine and Rehabilitation, School of MedicineUniversity of North Carolina Chapel HillChapel HillUSA

Personalised recommendations