Cancer is a multifactorial disease that is the second leading cause of death after cardiovascular disease in the world. In recent years, microbiota’s role in the regulation and homeostasis of the immune system has been considered. Moreover, the immune system can affect the microbiota content. These interactions are critical to the functioning of the immune system. Numerous studies in animal and human models have shown the association of changes in microbiota components with the formation of an inhibitory microenvironment in the tumor and its escape from the immune system. Microbiota also plays a crucial role in the success of various anti-tumor treatments, and its modification leads to success in cancer treatment. The success of anti-tumor therapies that directly target the immune system, such as immune checkpoint blockade and T cell therapy, is also affected by the patient’s microbiota composition. It seems that in addition to examining the patient’s genetics, precision medicine should pay attention to the patient’s microbiota in choosing the appropriate treatment method, and together with usual anti-tumor therapies, microbiota may be modified. This review discusses various aspects of the relationship between microbiota and anti-tumor immunity and its successful treatment.
Elinav E , Nowarski R , Thaiss CA , Hu B , Jin C , Flavell RA . Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 2013 Nov; 13(11): 759–771.
Medzhitov R . Origin and physiological roles of inflammation. Nature 2008 Jul 24; 454(7203): 428–435.
Martel C de , Ferlay J , Franceschi S , Vignat J , Bray F , Forman D , et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012 Jun 1; 13(6): 607–615.
Kallmeyer J , Pockalny R , Adhikari RR , Smith DC , D’Hondt S . Global distribution of microbial abundance and biomass in subseafloor sediment. Proc Natl Acad Sci U S A 2012 Oct 2; 109(40): 16213–16216.
Blaser MJ . Understanding microbe-induced cancers. Cancer Prev Res Phila Pa 2008 Jun; 1(1): 15–20.
Ojesina AI , Lichtenstein L , Freeman SS , Pedamallu CS , Imaz-Rosshandler I , Pugh TJ , et al. Landscape of genomic alterations in cervical carcinomas. Nature 2014 Feb 20; 506(7488): 371–375.
Guerra L , Guidi R , Frisan T . Do bacterial genotoxins contribute to chronic inflammation, genomic instability and tumor progression? FEBS J 2011 Dec; 278(23): 4577–4588.
Goodwin AC , Destefano Shields CE , Wu S , Huso DL , Wu X , Murray-Stewart TR , et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci U S A 2011 Sep 13; 108(37): 15354–15359.
Thompson MP , Kurzrock R . Epstein-Barr virus and cancer. Clin Cancer Res Off J Am Assoc Cancer Res 2004 Feb 1; 10(3): 803–821.
Abreu MT , Peek RM . Gastrointestinal malignancy and the microbiome. Gastroenterology 2014 May; 146(6): 1534–46.e3.
Hanahan D , Weinberg RA . The hallmarks of cancer. Cell 2000 Jan 7; 100(1): 57–70.
Kostic AD , Chun E , Robertson L , Glickman JN , Gallini CA , Michaud M , et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013 Aug 14; 14(2): 207–215.
Pikarsky E , Porat RM , Stein I , Abramovitch R , Amit S , Kasem S , et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004 Sep 23; 431(7007): 461–466.
Yu H , Pardoll D , Jove R . STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009 Nov; 9(11): 798–809.
Broder CC , Collman RG . Chemokine receptors and HIV. J Leukoc Biol 1997 Jul; 62(1): 20–29.
Knight SC , Macatonia SE , Patterson S . HIV I infection of dendritic cells. Int Rev Immunol 1990; 6(2–3): 163–175.
Garrett WS . Cancer and the microbiota. Science 2015 Apr 3; 348(6230): 80–86.
Yuan L , Zhang S , Li H , Yang F , Mushtaq N , Ullah S , et al. The influence of gut microbiota dysbiosis to the efficacy of 5-Fluorouracil treatment on colorectal cancer. Biomed Pharmacother Biomedecine Pharmacother 2018 Dec; 108: 184–193.
Schwabe RF , Jobin C . The microbiome and cancer. Nat Rev Cancer 2013 Nov; 13(11): 800–812.
Whisner CM , Athena Aktipis C . The role of the microbiome in cancer initiation and progression: How microbes and cancer cells utilize excess energy and promote one another’s growth. Curr Nutr Rep 2019 Mar 1; 8(1): 42–51.
Belkaid Y , Hand TW . Role of the microbiota in immunity and inflammation. Cell 2014 Mar 27; 157(1): 121–141.
Zhou B , Sun C , Huang J , Xia M , Guo E , Li N , et al. The biodiversity composition of microbiome in ovarian carcinoma patients. Sci Rep 2019 Feb 8; 9(1): 1691.
Wang H , Funchain P , Bebek G , Altemus J , Zhang H , Niazi F , et al. Microbiomic differences in tumor and paired-normal tissue in head and neck squamous cell carcinomas. Genome Med [Internet] 2017 Feb 7; 9. [cited 2019 May 9]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297129/.
Russo E , Bacci G , Chiellini C , Fagorzi C , Niccolai E , Taddei A , et al. Preliminary comparison of oral and intestinal human microbiota in patients with colorectal cancer: a pilot study. Front Microbiol [Internet] 2018; 8. [cited 2019 May 9]. Available from: https://www.frontiersin.org/articles/10.3389/fmicb.2017.02699/full.
Flemer B , Lynch DB , Brown JMR , Jeffery IB , Ryan FJ , Claesson MJ , et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut 2017 Apr 1; 66(4): 633–643.
Zhuang H , Cheng L , Wang Y , Zhang Y-K , Zhao M-F , Liang G-D , et al. Dysbiosis of the gut microbiome in lung cancer. Front Cell Infect Microbiol [Internet] 2019; 9. [cited 2019 May 9]. Available from: https://www.frontiersin.org/articles/10.3389/fcimb.2019.00112/full.
Fernández MF , Reina-Pérez I , Astorga JM , Rodríguez-Carrillo A , Plaza-Díaz J , Fontana L . Breast cancer and its relationship with the microbiota. Int J Environ Res Public Health [Internet] 2018 Aug; 15(8). [cited 2019 May 9]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121903/.
Bullman S , Pedamallu CS , Sicinska E , Clancy TE , Zhang X , Cai D , et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 2017 15; 358(6369): 1443–1448.
Schreiber RD , Old LJ , Smyth MJ . Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011 Mar 25; 331(6024): 1565–1570.
Dunn GP , Old LJ , Schreiber RD . The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22: 329–360.
Whiteside TL . Immune responses to malignancies. J Allergy Clin Immunol 2010 Feb; 125(2 Suppl 2): S272–S283.
Smyth MJ , Dunn GP , Schreiber RD . Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 2006; 90: 1–50.
Oikonomopoulou K , Brinc D , Kyriacou K , Diamandis EP . Infection and cancer: revaluation of the hygiene hypothesis. Clin Cancer Res 2013 Jun 1; 19(11): 2834–2841.
Vujanovic L , Mandic M , Olson WC , Kirkwood JM , Storkus WJ . A Mycoplasma peptide elicits heteroclitic CD4+ T cell responses against tumor antigen MAGE-A6. Clin Cancer Res 2007 Nov 15; 13(22): 6796–6806.
Vétizou M , Pitt JM , Daillère R , Lepage P , Waldschmitt N , Flament C , et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015 Nov 27; 350(6264): 1079–1084.
Zitvogel L , Ayyoub M , Routy B , Kroemer G . Microbiome and anticancer immunosurveillance. Cell 2016 Apr 7; 165(2): 276–287.
Wilson HL , Obradovic MR . Evidence for a common mucosal immune system in the pig. Mol Immunol 2015 Jul 1; 66(1): 22–34.
Wheeler R , Chevalier G , Eberl G , Gomperts Boneca I . The biology of bacterial peptidoglycans and their impact on host immunity and physiology. Cell Microbiol 2014 Jul 1; 16(7): 1014–1023.
Souza DG , Vieira AT , Soares AC , Pinho V , Nicoli JR , Vieira LQ , et al. The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J Immunol 2004 Sep 15; 173(6): 4137–4146.
Ganal SC , Sanos SL , Kallfass C , Oberle K , Johner C , Kirschning C , et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 2012 Jul 27; 37(1): 171–186.
Paulos CM , Wrzesinski C , Kaiser A , Hinrichs CS , Chieppa M , Cassard L , et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest 2007 Aug; 117(8): 2197–2204.
Rutkowski MR , Stephen TL , Svoronos N , Allegrezza MJ , Tesone AJ , Perales-Puchalt A , et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 2015 Jan 12; 27(1): 27–40.
Gagliani N , Hu B , Huber S , Elinav E , Flavell RA . The fire within: microbes inflame tumors. Cell 2014 May 8; 157(4): 776–783.
Muranski P , Boni A , Antony PA , Cassard L , Irvine KR , Kaiser A , et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008 Jul 15; 112(2): 362–373.
Grivennikov SI , Wang K , Mucida D , Stewart CA , Schnabl B , Jauch D , et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012 Nov 8; 491(7423): 254–258.
Chae W-J , Gibson TF , Zelterman D , Hao L , Henegariu O , Bothwell ALM . Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci U S A 2010 Mar 23; 107(12): 5540–5544.
Chae W-J , Bothwell ALM . Spontaneous intestinal tumorigenesis in Apc (/Min+) mice requires altered T cell development with IL-17A. J Immunol Res 2015; 2015: 860106.
Honda K , Littman DR . The microbiome in infectious disease and inflammation. Annu Rev Immunol 2012; 30: 759–795.
Scheiermann J , Klinman DM . Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer. Vaccine 2014 Nov 12; 32(48): 6377–6389.
Vicari AP , Chiodoni C , Vaure C , Aït-Yahia S , Dercamp C , Matsos F , et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti–interleukin 10 receptor antibody. J Exp Med 2002 Aug 19; 196(4): 541–549.
Iida N , Dzutsev A , Stewart CA , Smith L , Bouladoux N , Weingarten RA , et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013 Nov 22; 342(6161): 967–970.
Perez-Chanona E , Trinchieri G . The role of microbiota in cancer therapy. Curr Opin Immunol 2016 Apr; 39: 75–81.
Madondo MT , Quinn M , Plebanski M . Low dose cyclophosphamide: mechanisms of T cell modulation. Cancer Treat Rev 2016 Jan 1; 42: 3–9.
Kroemer G , Galluzzi L , Kepp O , Zitvogel L . Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31: 51–72.
Viaud S , Saccheri F , Mignot G , Yamazaki T , Daillère R , Hannani D , et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013 Nov 22; 342(6161): 971–976.
Nichols RG , Peters JM , Patterson AD . Interplay between the host, the human microbiome, and drug metabolism. Hum Genomics 2019 Jun 11; 13(1): 27.
Scott TA , Quintaneiro LM , Norvaisas P , Lui PP , Wilson MP , Leung K-Y , et al. Host-microbe Co-metabolism dictates cancer drug efficacy in C. elegans. Cell 2017 Apr 20; 169(3): 442–456.e18.
García-González AP , Ritter AD , Shrestha S , Andersen EC , Yilmaz LS , Walhout AJM . Bacterial metabolism affects the C. elegans response to cancer chemotherapeutics. Cell 2017 20; 169(3): 431–441.e8.
Yuan L , Zhang S , Li H , Yang F , Mushtaq N , Ullah S , et al. The influence of gut microbiota dysbiosis to the efficacy of 5-Fluorouracil treatment on colorectal cancer. Biomed Pharmacother Biomedecine Pharmacother 2018 Dec; 108: 184–193.
Gopalakrishnan V , Helmink BA , Spencer CN , Reuben A , Wargo JA . The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 2018 09; 33(4): 570–580.
Chaput N , Lepage P , Coutzac C , Soularue E , Le Roux K , Monot C , et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol Off J Eur Soc Med Oncol 2017 Jun 1; 28(6): 1368–1379.
Frankel AE , Coughlin LA , Kim J , Froehlich TW , Xie Y , Frenkel EP , et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017 Oct 1; 19(10): 848–855.
Gopalakrishnan V , Spencer CN , Nezi L , Reuben A , Andrews MC , Karpinets TV , et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018 05; 359(6371): 97–103.
Matson V , Fessler J , Bao R , Chongsuwat T , Zha Y , Alegre M-L , et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018 05; 359(6371): 104–108.
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 Jan 5; 359(6371): 91–97.
Uribe-Herranz M , Bittinger K , Rafail S , Guedan S , Pierini S , Tanes C , et al. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12. JCI Insight 2018 Feb 22; 3(4).
Smith M , Littmann E , Slingerland J , Clurman A , Slingerland AE , Taur Y , et al. Intestinal microbiome analyses identify biomarkers for patient response to CAR T cell therapy. Biol Blood Marrow Transpl 2019 Mar 1; 25(Suppl. 3): S177.
Kuntz TM , Gilbert JA . Introducing the microbiome into precision medicine. Trends Pharmacol Sci 2017; 38(1): 81–91.
Behrouzi A , Nafari AH , Siadat SD . The significance of microbiome in personalized medicine. Clin Transl Med 2019 May 13; 8(1): 16.
Eckert R , He J , Yarbrough DK , Qi F , Anderson MH , Shi W . Targeted killing of Streptococcus mutans by a pheromone-guided “smart” antimicrobial peptide. Antimicrob Agents Chemother 2006 Nov 1; 50(11): 3651–3657.
Cieplak T , Soffer N , Sulakvelidze A , Nielsen DS . A bacteriophage cocktail targeting Escherichia coli reduces E. coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota. Gut Microbes 2018 Aug 24; 9(5): 391–399.
Hill C , Guarner F , Reid G , Gibson GR , Merenstein DJ , Pot B , et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014 Aug; 11(8): 506–514.
Makras L , Triantafyllou V , Fayol-Messaoudi D , Adriany T , Zoumpopoulou G , Tsakalidou E , et al. Kinetic analysis of the antibacterial activity of probiotic lactobacilli towards Salmonella enterica serovar Typhimurium reveals a role for lactic acid and other inhibitory compounds. Res Microbiol 2006 Apr; 157(3): 241–247.
Rossi M , Mirbagheri S , Keshavarzian A , Bishehsari F . Nutraceuticals in colorectal cancer: a mechanistic approach. Eur J Pharmacol 2018 Aug 15; 833: 396–402.
Ambalam P , Raman M , Purama RK , Doble M . Probiotics, prebiotics and colorectal cancer prevention. Best Pract Res Clin Gastroenterol 2016 Feb; 30(1): 119–131.
Goldin BR , Gorbach SL . The effect of milk and lactobacillus feeding on human intestinal bacterial enzyme activity. Am J Clin Nutr 1984 May; 39(5): 756–761.
Morotomi M , Mutai M . In vitro binding of potent mutagenic pyrolysates to intestinal bacteria. J Natl Cancer Inst 1986 Jul; 77(1): 195–201.
Pithva SP , Ambalam PS , Ramoliya JM , Dave JM , Vyas BRM . Antigenotoxic and antimutagenic activities of probiotic Lactobacillus rhamnosus Vc against N-Methyl-N’-Nitro-N-Nitrosoguanidine. Nutr Cancer 2015; 67(7): 1142–1150.
Kumar A , Singh NK , Sinha PR . Inhibition of 1,2-dimethylhydrazine induced colon genotoxicity in rats by the administration of probiotic curd. Mol Biol Rep 2010 Mar; 37(3): 1373–1376.
Nowak A , Kuberski S , Libudzisz Z . Probiotic lactic acid bacteria detoxify N-nitrosodimethylamine. Food Addit Contam Part Chem Anal Control Expo Risk Assess 2014; 31(10): 1678–1687.
Horie H , Zeisig M , Hirayama K , Midtvedt T , Möller L , Rafter J . Probiotic mixture decreases DNA adduct formation in colonic epithelium induced by the food mutagen 2-amino-9H-pyrido[2,3-b]indole in a human-flora associated mouse model. Eur J Cancer Prev Off J Eur Cancer Prev Organ ECP 2003 Apr; 12(2): 101–107.
Orrhage K , Sillerström E , Gustafsson JA , Nord CE , Rafter J . Binding of mutagenic heterocyclic amines by intestinal and lactic acid bacteria. Mutat Res 1994 Dec 1; 311(2): 239–248.
Gamallat Y , Meyiah A , Kuugbee ED , Hago AM , Chiwala G , Awadasseid A , et al. Lactobacillus rhamnosus induced epithelial cell apoptosis, ameliorates inflammation and prevents colon cancer development in an animal model. Biomed Pharmacother Biomedecine Pharmacother 2016 Oct; 83: 536–541.
Kuugbee ED , Shang X , Gamallat Y , Bamba D , Awadasseid A , Suliman MA , et al. Structural change in microbiota by a probiotic cocktail enhances the gut barrier and reduces cancer via TLR2 signaling in a rat model of colon cancer. Dig Dis Sci 2016; 61(10): 2908–2920.
Ma EL , Choi YJ , Choi J , Pothoulakis C , Rhee SH , Im E . The anticancer effect of probiotic Bacillus polyfermenticus on human colon cancer cells is mediated through ErbB2 and ErbB3 inhibition. Int J Cancer 2010 Aug 15; 127(4): 780–790.
Kim H-S , Park H , Cho I-Y , Paik H-D , Park E . Dietary supplementation of probiotic Bacillus polyfermenticus, Bispan strain, modulates natural killer cell and T cell subset populations and immunoglobulin G levels in human subjects. J Med Food 2006; 9(3): 321–327.
Manuzak JA , Hensley-McBain T , Zevin AS , Miller C , Cubas R , Agricola B , et al. Enhancement of microbiota in healthy macaques results in beneficial modulation of mucosal and systemic immune function. J Immunol Baltim Md 1950 2016 Mar 1; 196(5): 2401–2409.
Chen D , Wu J , Jin D , Wang B , Cao H . Fecal microbiota transplantation in cancer management: current status and perspectives. Int J Cancer 2019 Oct 15; 145(8): 2021–2031.
Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies -- draft guidance for industry: 6.
Rosshart SP , Vassallo BG , Angeletti D , Hutchinson DS , Morgan AP , Takeda K , et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell 2017 Nov 16; 171(5): 1015–1028.e13.
Kao D , Roach B , Park H , Hotte N , Madsen K , Bain V , et al. Fecal microbiota transplantation in the management of hepatic encephalopathy. Hepatol Baltim Md 2016 Jan; 63(1): 339–340.
Cui M , Xiao H , Li Y , Zhou L , Zhao S , Luo D , et al. Faecal microbiota transplantation protects against radiation‐induced toxicity. EMBO Mol Med 2017 Apr; 9(4): 448–461.
Bastard QL , Ward T , Sidiropoulos D , Hillmann BM , Chun CL , Sadowsky MJ , et al. Fecal microbiota transplantation reverses antibiotic and chemotherapy-induced gut dysbiosis in mice. Sci Rep 2018 Apr 18; 8(1): 1–11.
Suez J , Zmora N , Zilberman-Schapira G , Mor U , Dori-Bachash M , Bashiardes S , et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell 2018 06; 174(6): 1406–1423.e16.