Reprogramming of Tumor Associated Immune Cells by Phytochemicals: In-vitro Approaches for Cancer Treatment

  • Pradip Kumar Jaiswara
  • Vishal Kumar Gupta
  • Shiv Govind Rawat
  • Pratishtha Sonker
  • Ajay KumarEmail author


In recent years, phytochemicals have emerged as potential therapeutic agents against various diseases such as diabetes, microbial infections and cancer due to their minimum side effects and low cost. Plant-derived molecules improve disease conditions either directly or indirectly via targeting disease-causing factors or boosting the immune system. The immunomodulatory actions of phytochemicals play a vital role in the improvement of diabetes, microbial diseases, and cancer. Further, immunomodulatory properties of phytochemicals have been observed in tumor-bearing hosts. Therefore, phytochemicals with immunomodulatory properties are emerging as immunotherapeutic agents against cancer. The present book chapter discusses the in vitro immunomodulatory properties of phytochemicals against tumor-associated immune cells and associated mechanisms.


Cancer immunotherapy Immunomodulation Phytochemicals Tumor-associated immune cells 



We thankfully acknowledge fellowship support to Pradip Kumar Jaiswara [Award No. 1002/(SC)(CSIR-UGC NET DEC. 2016] and Shiv Govind Rawat [Award No. 09/013(0772/2018-EMR-I)] from CSIR, New Delhi and Pratishtha Sonker [Award No. F117.1/201516/RGNF201517SCUTT4822/(SAIII/Website)] from UGC, New Delhi. Funding from University Grants Commission and Department of Science & Technology, New Delhi, India, in the form of UGC-Start-Up Research (F. No. 30-370/2017 (BSR)) and Early Career Research Award (ECR/2016/001117) is highly acknowledged. Financial support from ISLS and UGC-UPE, Banaras Hindu University is also acknowledged. We also acknowledge UGC-CAS and DST-FIST program to the Department of Zoology, Banaras Hindu University, India.


  1. Adeonipekun PA, Adeniyi TA, David ED. Antimicrobial properties and melissopalynology, proximate and elemental analyses of honey samples from three different ecozones in Nigeria. Notulae Sci Biol. 2016;8(3):326–33. Scholar
  2. Bae JH, Kim JY, Kim MJ, Chang SH, Park YS, Son CH, Park SJ, Chung JS, Lee EY, Kim SH, Kang CD. Quercetin enhances susceptibility to NK cell-mediated lysis of tumor cells through induction of NKG2D ligands and suppression of HSP70. J Immunother. 2010;33:391–401. Scholar
  3. Balsamo M, Vermi W, Parodi M, Pietra G, Manzini C, Queirolo P, Lonardi S, Augugliaro R, Moretta A, Facchetti F, Moretta L, Mingari MC, Vitale M. Melanoma cells become resistant to NK-cell-mediated killing when exposed to NK-cell numbers compatible with NK-cell infiltration in the tumor. Eur J Immunol. 2012;42(7):1833–42. Scholar
  4. Bhattacharyya S, Mandal D, Saha B, Sen GS, Das T, Sa G. Curcumin prevents tumor-induced T cell apoptosis through Stat-5a-mediated Bcl-2 induction. J Biol Chem. 2007;282(22):15954–64. Scholar
  5. Bhattacharyya S, Md Sakib Hossain D, Mohanty S, Sankar Sen G, Chattopadhyay S, Banerjee S, Chakraborty J, Das K, Sarkar D, Das T, Sa G. Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cell Mol Immunol. 2010;7(4):306–15. Scholar
  6. Bhaumik S, Jyothi MD, Khar A. Differential modulation of nitric oxide production by curcumin in host macrophages and NK cells. FEBS Lett. 2000;483(1):78–82. Scholar
  7. Bill MA, Bakan C, Benson DM Jr, Fuchs J, Young G, Lesinski GB. Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines. Mol Cancer Ther. 2009;8(9):2726–35. Scholar
  8. Brouet I, Ohshima H. Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages. Biochem Biophys Res Commun. 1995;206(2):533–40. Scholar
  9. Burkard M, Leischner C, Lauer UM, Busch C, Venturelli S, Frank J. Dietary flavonoids and modulation of natural killer cells: implications in malignant and viral diseases. J Nutr Biochem. 2017;46:1–12. Scholar
  10. Carrero P, Ortega H, Martinez-Botas J, Gomez-Coronado D, Lasuncion MA. Flavonoid-induced ability of minimally modified low-density lipoproteins to support lymphocyte proliferation. Biochem Pharmacol. 1998;55(7):1125–9. Scholar
  11. Caspi RR. Immunotherapy of autoimmunity and cancer: the penalty for success. Nat Rev Immunol. 2008;8(12):970–6. Scholar
  12. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3–23. Scholar
  13. Chen D, Nie M, Fan MW, Bian Z. Anti-inflammatory activity of curcumin in macrophages stimulated by lipopolysaccharides from Porphyromonas gingivalis. Pharmacology. 2008;82(4):264–9. Scholar
  14. Chew V, Toh HC, Abastado JP. Immune microenvironment in tumor progression: characteristics and challenges for therapy. J Oncol. 2012;2012:608406. Scholar
  15. Corthay A. How do regulatory T cells work? Scand J Immunol. 2009;70(4):326–36. Scholar
  16. Cundell RD. Herbal phytochemicals as immunomodulators. Curr Immunol Rev. 2014;10(2):64–81. Scholar
  17. Dahlberg CI, Sarhan D, Chrobok M, Duru AD, Alici E. Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity. Front. Immunol. 2015;6:605.
  18. Devaud C, John LB, Westwood JA, Darcy PK, Kershaw MH. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. Oncoimmunology. 2013;2(8):e25961. Scholar
  19. Driessens G, Kline J, Gajewski TF. Costimulatory and coinhibitory receptors in anti-tumor immunity. Immunol Rev. 2009;229(1):126–44. Scholar
  20. Espinoza JL, Nguyen VH, Ichimura H, Pham TT, Nguyen CH, Pham TV, Elbadry MI, Yoshioka K, Tanaka J, Trung LQ, Takami A, Nakao S. A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers. Sci Rep. 2016;6:39231. Scholar
  21. Falchetti R, Fuggetta MP, Lanzilli G, Tricarico M, Ravagnan G. Effects of resveratrol on human immune cell function. Life Sci. 2001;70(1):81–96. Scholar
  22. Fiala M. Curcumin and omega-3 fatty acids enhance NK cell-induced apoptosis of pancreatic cancer cells but curcumin inhibits interferon-gamma production: benefits of omega-3 with curcumin against cancer. Molecules. 2015;20(2):3020–6. Scholar
  23. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22. Scholar
  24. Gao S, Zhou J, Liu N, Wang L, Gao Q, Wu Y, Zhao Q, Liu P, Wang S, Liu Y, Guo N, Shen Y, Yuan Z. Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13. J Mol Cell Cardiol. 2015;85:131–9. Scholar
  25. Giurisato E, Xu Q, Lonardi S, Telfer B, Russo I, Pearson A, Finegan KG, Wang W, Wang J, Gray NS, Vermi W, Xia Z, Tournier C. Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition. Proc Natl Acad Sci U S A. 2018;115(12):E2801–10. Scholar
  26. Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 2016;17(9):1025–36. Scholar
  27. Halder RC, Almasi A, Sagong B, Leung J, Jewett A, Fiala M. Curcuminoids and omega-3 fatty acids with anti-oxidants potentiate cytotoxicity of natural killer cells against pancreatic ductal adenocarcinoma cells and inhibit interferon gamma production. Front Physiol. 2015;6:129. Scholar
  28. Han R, Wu WQ, Wu XP, Liu CY. Effect of total flavonoids from the seeds of Astragali complanati on natural killer cell function. J Ethnopharmacol. 2015;173:157–65. Scholar
  29. Her M, Kavanaugh A. Alterations in immune function with biologic therapies for autoimmune disease. J Allergy Clin Immunol. 2016;137(1):19–27. Scholar
  30. Hou D, Wang D, Ma X, Chen W, Guo S, Guan H. Effects of total flavonoids of sea buckthorn (Hippophae rhamnoides L.) on cytotoxicity of NK92-MI cells. Int J Immunopathol Pharmacol. 2017;30(4):353–61. Scholar
  31. Kim HP, Son KH, Chang HW, Kang SS. Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci. 2004; 96(3):229–45.CrossRefGoogle Scholar
  32. Kliem C, Merling A, Giaisi M, Kohler R, Krammer PH, Li-Weber M. Curcumin suppresses T cell activation by blocking Ca2+ mobilization and nuclear factor of activated T cells (NFAT) activation. J Biol Chem. 2012;287(13):10200–9. Scholar
  33. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J. 2013;2013:162750. Scholar
  34. Langers I, Renoux VM, Thiry M, Delvenne P, Jacobs N. Natural killer cells: role in local tumor growth and metastasis. Biologics: Targets Ther. 2012;6:73–82. Scholar
  35. Lee HH, Cho H. Improved anti-cancer effect of curcumin on breast cancer cells by increasing the activity of natural killer cells. J Microbiol Biotechnol. 2018;28(6):874–82. Scholar
  36. Lee JK, Kim SY, Kim YS, Lee WH, Hwang DH, Lee JY. Suppression of the TRIF-dependent signaling pathway of Toll-like receptors by luteolin. Biochem Pharmacol. 2009;77(8):1391–400. Scholar
  37. Leiro J, Alvarez E, Garcia D, Orallo F. Resveratrol modulates rat macrophage functions. Int Immunopharmacol. 2002;2(6):767–74. Scholar
  38. Li Q, Huyan T, Ye LJ, Li J, Shi JL, Huang QS. Concentration-dependent biphasic effects of resveratrol on human natural killer cells in vitro. J Agric Food Chem. 2014;62(45):10928–35. Scholar
  39. Lopez-Posadas R, Ballester I, Abadia-Molina AC, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F. Effect of flavonoids on rat splenocytes, a structure-activity relationship study. Biochem Pharmacol. 2008;76(4):495–506. Scholar
  40. Lu CC, Chen JK. Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways. J Cell Physiol. 2010;223(2):343–51. Scholar
  41. Mandal A, Viswanathan C. Natural killer cells: in health and disease. Hematol Oncol Stem Cell Ther. 2015;8(2):47–55. Scholar
  42. Murr C, Schroecksnadel K, Winkler C, Ledochowski M, Fuchs D. Antioxidants may increase the probability of developing allergic diseases and asthma. Med Hypotheses. 2005;64(5):973–7. Scholar
  43. Nagendran J, Bleackley C, Ross DB, West LJ, Dyck JR. Resveratrol attenuates stimulated t-cells activation and proliferation: a novel therapy against cellular rejection in cardiac transplantation. J Heart Lung Transplant. 2013;32(4S):S248–9. Scholar
  44. Nair MP, Mahajan S, Reynolds JL, Aalinkeel R, Nair H, Schwartz SA, Kandaswami C. The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system. Clin Vaccine Immunol. 2006;13(3):319–28. Scholar
  45. Nielsen SR, Schmid MC. Macrophages as key drivers of cancer progression and metastasis. Mediat Inflamm. 2017;2017:9624760. Scholar
  46. Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:e47. Scholar
  47. Richards DM, Hettinger J, Feuerer M. Monocytes and macrophages in cancer: development and functions. Cancer Microenviron. 2013;6(2):179–91. Scholar
  48. Roszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediat Inflamm. 2015;2015:816460. Scholar
  49. Schwager J, Richard N, Widmer F, Raederstorff D. Resveratrol distinctively modulates the inflammatory profiles of immune and endothelial cells. BMC Complement Altern Med. 2017;17(1):309.
  50. Seager RJ, Hajal C, Spill F, Kamm RD, Zaman MH. Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression. Converg Sci Phys Oncol. 2017;3:034002. Scholar
  51. Shukla S, Mehta A. Comparative phytochemical analysis and in vivo immunomodulatory activity of various extracts of Stevia rebaudiana leaves in experimental animal model. Front Life Sci. 2014;8(1):55–63. Scholar
  52. Sithranga Boopathy N, Kathiresan K. Anticancer drugs from marine flora: an overview. J Oncol. 2010;2010:214186. Scholar
  53. Smith HA, Kang Y. The metastasis-promoting roles of tumor-associated immune cells. J Mol Med (Berl). 2013;91(4):411–29. Scholar
  54. Sun L, Chen B, Jiang R, Li J, Wang B. Resveratrol inhibits lung cancer growth by suppressing M2-like polarization of tumor associated macrophages. Cell Immunol. 2017;311:86–93. Scholar
  55. Sungur CM, Murphy WJ. Positive and negative regulation by NK cells in cancer. Crit Rev Oncog. 2014;19(1–2):57–66. Scholar
  56. Verbeek R, Plomp AC, van Tol EA, van Noort JM. The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells. Biochem Pharmacol. 2004;68(4):621–9. Scholar
  57. Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene. 2008;27(45):5932–43. Scholar
  58. Watson JL, Vicario M, Wang A, Moreto M, McKay DM. Immune cell activation and subsequent epithelial dysfunction by Staphylococcus enterotoxin B is attenuated by the green tea polyphenol (-)-epigallocatechin gallate. Cell Immunol. 2005;237(1):7–16. Scholar
  59. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27(45):5904–12. Scholar
  60. Wolowczuk I, Verwaerde C, Viltart O, Delanoye A, Delacre M, Pot B, Grangette C. Feeding our immune system: impact on metabolism. Clin Dev Immunol. 2008;2008:639803. Scholar
  61. Wong GK, Heather JM, Barmettler S, Cobbold M. Immune dysregulation in immunodeficiency disorders: the role of T-cell receptor sequencing. J Autoimmun. 2017;80:1–9. Scholar
  62. Wu J, Lanier LL. Natural killer cells and cancer. Adv Cancer Res. 2003;90:127–56. Scholar
  63. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10(1):58. Scholar
  64. 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. Scholar
  65. Yuan Y, Jiang YC, Sun CK, Chen QM. Role of the tumor microenvironment in tumor progression and the clinical applications (review). Oncol Rep. 2016;35:2499–515. Scholar
  66. Zamai L, Ahmad M, Bennett IM, Azzoni L, Alnemri ES, Perussia B. Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J Exp Med. 1998;188(12):2375–80. Scholar
  67. Zhao GJ, Lu ZQ, Tang LM, Wu ZS, Wang DW, Zheng JY, Qiu QM. Curcumin inhibits suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. Int Immunopharmacol. 2012;14(1):99–106. Scholar
  68. Zhou Y, Zhang T, Wang X, Wei X, Chen Y, Guo L, Zhang J, Wang C. Curcumin modulates macrophage polarization through the inhibition of the toll-like receptor 4 expression and its signaling pathways. Cell Physiol Biochem. 2015;36(2):631–41. Scholar
  69. Zou T, Yang Y, Xia F, Huang A, Gao X, Fang D, Xiong S, Zhang J. Resveratrol inhibits CD4+ T cell activation by enhancing the expression and activity of Sirt1. PLoS One. 2013;8(9):e75139. Scholar
  70. Zou JY, Su CH, Luo HH, Lei YY, Zeng B, Zhu HS, Chen ZG. Curcumin converts Foxp3+ regulatory T cells to T helper 1 cells in patients with lung cancer. J Cell Biochem. 2018;119(2):1420–8. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Pradip Kumar Jaiswara
    • 1
  • Vishal Kumar Gupta
    • 1
  • Shiv Govind Rawat
    • 1
  • Pratishtha Sonker
    • 1
  • Ajay Kumar
    • 1
    Email author
  1. 1.Department of ZoologyBanaras Hindu UniversityVaranasiIndia

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