Hydrogen peroxide impedes NK cell and T cell mediated cytotoxicity against colon cancer cell
Although hydrogen peroxide (H2O2) is an admirable treatment for many cancer types, but the clinical impact of H2O2 on immune cells is not known. In the present study, we have demonstrated that H2O2 is a crucial factor to determine the cell mediated cytotoxicity of immune cells to the cancer cells. Natural killer (NK) cells and T cells were isolated from healthy donors and were activated and enriched the population at ex-vivo condition. At day14, activated NK and T cells were exposed to colon cancer cell at the ratio of 10:1 (Effector: Target) with or without H2O2 (50 µM and 100µM) treatment for 6 h and 12 h. Cytotoxicity assay showed that cytotolytic ability of NK and T cells was strongly suppressed in the presence of H2O2. H2O2 induced NK and T cell dysfunction was analyzed and results demonstrated that NK and T cells were lose their viability on dose and time dependent manner. Also, flow cytometry analysis revealed that H2O2 significantly suppresses the activation and proliferation CD8 T cell population. Whereas, NK cell subset (CD56bright and CD56dim) was dramatically altered by H2O2. When exposed to H2O2, CD56dim population was considerably increased at different time points. Hence, we conclude that H2O2 directly or functionally defect the NK and T cell mediated cytotoxicity and however, further studies are warranted to confirm the concept with mild dose of H2O2 with different cancer cell lines.
Ahmad KA, Iskandar KB, Hirpara JL, et al. Hydrogen peroxide-mediated cytosolic acidification is a signal for mitochondrial translocation of Bax during drug-induced apoptosis of tumor cells. Cancer Res. 2004; 1 64(21):7867-78.
Alexandre J, Nicco C, Chereau C, et al. Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir. J Natl Cancer Inst. 2006; 6: 236-244.
Arbiser JL, Petros J, Klafter R, et al. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci. 2002; 99: 715-720.
Betten A, Dahlgren C, Mellqvist UH, et al. Oxygen radical-induced natural killer cell dysfunction: role of myeloperoxidase and regulation by serotonin. Journal of Leukocyte Biology. 2004; 75(6):1111-1115.
Broere F, Apasov SG, Sitkovsky MV, et al. T cell subsets and T cell-mediated immunity. Principles of Immunopharmacology: 3rd revised and extended edition. 2011.
Chen Q, Espey MG, Krishna MC, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci. 2005; 102(38): 13604-13609.
Clement MV, Hirpara JL, Pervaiz S. Decrease in intracellular superoxide sensitizes Bcl-2-overexpressing tumor cells to receptor and drug-induced apoptosis independent of the mitochondria. Cell Death & Differentiation. 2003; 10(11): 1273-1285.
Del Bello B, Paolicchi A, Comporti M, et al. Hydrogen peroxide produced during gamma-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintenance of proliferation in U937 cells. FASEB J. 1999; 13:69-79.
Fredrik B, Thoren Ana I, Romero, et al. Oxygen Radicals Induce Poly(ADP-Ribose) Polymerase-Dependent Cell Death in Cytotoxic Lymphocytes. The Journal of Immunology. 2006; 176: 7301–7307.
Liou GY, Storz P. Reactive oxygen species in cancer. Free Radical Research. 2010; 44(5):479-496.
Hansson M, Hermodsson S, Brune M, et al. Histamine protects T cells and natural killer cells against oxidative stress. Journal of Interferon Cytokine Research. 1999; 19:1135-1144.
Harlin H, Hanson M, Johansson CC, et al. The CD16-CD56bright NK cell subset is resistant to reactive oxygen species produced by activated granulocytes and has higher antioxidative capacity than the CD16+CD56dim subset. Journal of Immunology. 2007; 179:4513-4519.
Hirpara JL, Clement MV, Pervaiz S. Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells. Journal of Biological Chemistry. 2001; 276(1):514-521.
Kono K, Salazar-Onfray F, Petersson M, et al. Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. European Journal of Immunology. 1996; 26(6):1308-1313.
Lanier L. Turning on natural killer cells. Journal of Experimental Medicine. 2006; 191: 1259–1262
Lee YS, Kang YS, Lee SH, et al. Role of NAD(P)H oxidase in the tamoxifen-induced generation of reactive oxygen species and apoptosis in HepG2 human hepatoblastoma cells. Cell Death & Differentiation. 2000; 7:925-932.
Lopez-Lazaro M. Dual role of hydrogen peroxide in cancer: Possible relevance to cancer chemoprevention and therapy. Cancer Letters. 2007; 252: 1-8.
Moretta L, Moretta A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J. 2004; 23:255-259.
Nelson KK, Ranganathan AC, Mansouri J, et al. Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis. Clinical Cancer Research. 2003; 9(1):424-432.
Nicco C, Laurent A, Chereau C, et al. Differential modulation of normal and tumor cell proliferation by reactive oxygen species. Biomedicine & Pharmacotherapy. 2005; 59(4):169-174.
Polytarchou, C, Polytarchou M, Polytarchou E. Hydrogen peroxide stimulates proliferation and migration of human prostate cancer cells through activation of activator protein 1 and up-regulation of the heparin affin regulatory peptide gene. Journal of Biological Chemistry. 2005; 280:40428-40435.
Rieber M, Strasberg-Rieber M. Hypoxia, Mn-SOD and H2O2 regulate p53 reactivation and PRIMA-1 toxicity irrespective of p53 status in human breast cancer cells. Biochemical Pharmacology. 2012; 84:1563–1570.
Shafer-Weaver KA, Sayers T, Kuhns DB, et al. Evaluating the cytotoxicity of innate immune effector cells using the GrB ELISPOT assay. Journal of Translational Medicine. 2004; 2(1): 31.
Subramani B, Pullai CR, Krishnan K, et al. Efficacy of ex vivo activated and expanded natural killer cells and T lymphocytes for colorectal cancer patients. Biomedical Reports. 2014; 2: 505-508.
Ratnavelu K, Subramani B, Pullai CR, et al. Autologous immune enhancement therapy against an advanced epithelioid sarcoma: A case report. Oncol Lett. 2013; 5:1457-1460.
Takada M, Terunuma H, Deng X, et al. Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach. Breast Cancer. 2011; 18: 64- 67.
Copyright (c) 2019 EPH - International Journal of Biological & Pharmaceutical Science (ISSN: 2208-2166)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
- All contributor(s) agree to transfer the copyright of this article to EPH Journal.
- EPH Journal will have all the rights to distribute, share, sell, modify this research article with proper reference of the contributors.
- EPH Journal will have the right to edit or completely remove the published article on any misconduct happening.