The effect of redox bacteria on the programmed cell death-1 cancer immunotherapy

Majid Nejati , Masoud Soheili, Mostafa Khedri


Background and purpose: Extracellular electron transferring (EET) or redox bacteria employ a shuttle of flavins to transfer electrons to the oxygen in the intestinal mucosa. Although clinical studies suggest that the gut microbiome modulates the efficiency of immune checkpoint therapy in patients with cancer, the modulation mechanisms have not been well-characterized yet.

Experimental approach: In the present study, the oral gavage administration of Shewanella oneidensis                MR-1 as a prototypic EET bacteria was assayed in a mouse model of lung cancer to determine the                                       effect of EET bacterium on the efficacy of the programmed cell death protein 1 (PD1)-immune checkpoint therapy.

Findings/Results: It was indicated that in vitro EET from S. oneidensis was mediated by riboflavins that were supplied through extrinsic sources. Co-administration of S. oneidensis and anti-PD1 antibodies represent better tumor remission compared to the single-administration of each one; however, no statistically significant change was observed in the tumor volume.  

Conclusion and implications: More detailed studies are needed to definitively confirm the therapeutic effects of electrogenic bacteria in patients with cancer. Given the findings of the present study, increasing flavin compounds or EET bacteria in the intestine may provide novel strategies for modulating cancer immunotherapy.




Cancer immunotherapy; Electrogenic bacteria; Programmed cell death protein-1.

Full Text:



Khedri M, Rafatpanah H, Abnous K, Ramezani P, Ramezani M. Cancer immunotherapy via nucleic acid aptamers. Int J Immunopharmacol. 2015;29(2):926-36.DOI: 10.1016/j.intimp.2015.10.013.

Khedri M, Abnous K, Rafatpanah H, Nabavinia MS, Taghdisi SM, Ramezani M. Development and evaluation of novel aptamers specific for human PD1 using hybrid systematic evolution of ligands by exponential enrichment approach. Immunol Invest. 2020;49(5):535-554.DOI: 10.1080/08820139.2020.1744639.

Samei A, Khedri M. Gut microbiota modulates the efficiency of programmed cell death protein 1 cancer immunotherapies. Iran J Allergy Asthma Immunol. 2022;21(1):1-11.DOI: 10.18502/ijaai.v21i1.8607.

Daillère R, Vétizou M, Waldschmitt N, Yamazaki T, Isnard C, Poirier-Colame V, et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity. 2016;45(4):931-943.DOI: 10.1016/j.immuni.2016.09.009.

Zitvogel L, Ayyoub M, Routy B, Kroemer G. Microbiome and anticancer immunosurveillance. Cell. 2016;165(2):276-287.DOI: 10.1016/j.cell.2016.03.001.

Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-y M, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341(6145):569-573.DOI: 10.1126/science.1241165.

Xu X, Lv J, Guo F, Li J, Jia Y, Jiang D, et al. Gut microbiome influences the efficacy of PD-1 antibody immunotherapy on MSS-type colorectal cancer via metabolic pathway. Front Microbiol. 2020;11:814,1-18.DOI: 10.3389/fmicb.2020.00814.

Hatae R, Chamoto K, Kim YH, Sonomura K, Taneishi K, Kawaguchi S, et al. Combination of host immune metabolic biomarkers for the PD-1 blockade cancer immunotherapy. JCI Insight. 2020;5(2):e133501,1-18.DOI: 10.1172/jci.insight.133501.

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.DOI: 10.1126/science.aan3706.

Kato S. Biotechnological aspects of microbial extracellular electron transfer. Microbes Environ. 2015;30(2):133-139.DOI: 10.1264/jsme2.ME15028.

Levin M, Pezzulo G, Finkelstein JM. Endogenous bioelectric signaling networks: exploiting voltage gradients for control of growth and form. Annu Rev Biomed Eng. 2017;19:353-387.DOI: 10.1146/annurev-bioeng-071114-040647.

Robinson AJ, Jain A, Sherman HG, Hague RJ, Rahman R, Sanjuan‐Alberte P, et al. Toward hijacking bioelectricity in cancer to develop new bioelectronic medicine. Adv Ther. 2021;4(3):2000248,1-18.DOI: 10.1002/adtp.202000248.

Crane F, Low H, Navas P, Sun IL. Control of cell growth by plasma membrane NADH oxidation. Pure Appl Chem. 2013;1:31-42.DOI: 10.12988/pacs.2013.3310.

Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73(1):128-138.DOI: 10.1158/0008-5472.CAN-12-2606.

Sadraeian M, Khoshnood Mansoorkhani MJ, Mohkam M, Rasoul-Amini S, Hesaraki M, Ghasemi Y. Prevention and inhibition of TC-1 cell growth in tumor bearing mice by HPV16 E7 protein in fusion with Shiga toxin B-subunit from Shigella

dysenteriae. Cell J (Yakhteh). 2013;15(2):176-181.PMID: 23862120.

Khan MT, Duncan SH, Stams AJM, Van Dijl JMV, Flint HJ, Harmsen HJ. The gut anaerobe Faecalibacterium prausnitzii uses an extracellular electron shuttle to grow at oxic–anoxic interphases. ISME J. 2012;6(8):1578-1585.DOI: 10.1038/ismej.2012.5.

Kwolek-Mirek M, Zadrag-Tecza R. Comparison of methods used for assessing the viability and vitality of yeast cells. FEMS Yeast Res. 2014;14(7):1068-1079.DOI: 10.1111/1567-1364.12202.

Logan BE, Regan J. Microbial fuel cells-challenges and applications. Environ Sci Technol.; 2006;40(17):5172-5180.DOI: 10.1021/es0627592.

Light SH, Su L, Rivera-Lugo R, Cornejo JA, Louie A, Iavarone AT, et al. A flavin-based extracellular electron transfer mechanism in diverse gram-positive bacteria. Nature. 2018;562(7725):140-144.DOI: 10.1038/s41586-018-0498-z.

Masuda M, Freguia S, Wang YF, Tsujimura S, Kano K. Flavins contained in yeast extract are exploited for anodic electron transfer by Lactococcus lactis. Bioelectrochemistry. 2010;78(2):173-175.DOI: 10.1016/j.bioelechem.2009.08.004.

Okamoto A, Hashimoto K, Nealson KH, Nakamura R. Rate enhancement of bacterial extracellular electron transport involves bound flavin semiquinones. Proc Natl Acad Sci. 2013;110(19):7856-7561.DOI: 10.1073/pnas.1220823110.

Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314(23):2535-2543.DOI: 10.1001/jama.2015.16669.

Liu B, Rotenberg SA, Mirkin MV. Scanning electrochemical microscopy of living cells: different redox activities of nonmetastatic and metastatic human breast cells. Proc Natl Acad Sci. 2000;97(18):9855-9860.DOI: 10.1073/pnas.97.18.985.

Paré JF, Martyniuk CJ, Levin M. Bioelectric regulation of innate immune system function in regenerating and intact Xenopus laevis. NPJ Regen Med. 2017;2:1-15.DOI: 10.1038/s41536-017-0019-y.

Johansson-Lindbom B, Agace WW. Vitamin A helps gut T cells find their way in the dark. Nat Med. 2004;10(12):1300-1301.DOI: 10.1038/nm1204-1300.


  • There are currently no refbacks.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.