Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy

Abstract

The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

Keywords

tumor immunotherapy / immune checkpoint inhibitor / antibiotics / gut microbiota / drug–drug interaction

References

[1] Xu BB, He YJ, Wang WL, Zhou CF, Xie SC, Shen DY, Lmcleod H. Research progress of immune checkpoint therapy for cancer. Chin J Clin Pharm Ther (Zhongguo Lin Chuang Yao Li Xue Yu Zhi Liao Xue) 2016; 21(2): 218−234 (in Chinese)

[2] Chen P, Lin JG, Dai YB, Zhao AY, Dai YJ, Xu TW. Progress in understanding the relationship between gut microbiota and immune checkpoint inhibitors. Chin J Clin Oncol (Zhongguo Zhong Liu Lin Chuang) 2019; 46(24): 1292−1296 (in Chinese)

[3] DarvinP, ToorSM, Sasidharan NairV, ElkordE. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018; 50( 12): 1– 11

[4] ZhaoS, GaoG, LiW, LiX, ZhaoC, JiangT, JiaY, HeY, LiA, SuC, RenS, ChenX, ZhouC. Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer. Lung Cancer 2019; 130 : 10– 17

[5] RotteA. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 2019; 38( 1): 255

[6] Herrera-CamachoI, Anaya-RuizM, Perez-SantosM, Millán-PérezPeña L, BandalaC, LandetaG. Cancer immunotherapy using anti-TIM3/PD-1 bispecific antibody: a patent evaluation of EP3356411A1. Expert Opin Ther Pat 2019; 29( 8): 587– 593

[7] DatarI, SanmamedMF, WangJ, HenickBS, ChoiJ, BadriT, DongW, ManiN, TokiM, MejíasLD, LozanoMD, Perez-GraciaJL, VelchetiV, HellmannMD, GainorJF, McEachernK, JenkinsD, SyrigosK, PolitiK, GettingerS, RimmDL, HerbstRS, MeleroI, ChenL, SchalperKA. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res 2019; 25( 15): 4663– 4673

[8] McCarthyMW, WalshTJ. Checkpoint inhibitors and the risk of infection. Expert Rev Precis Med Drug Dev 2017; 2( 5): 287– 293

[9] RuffoE, WuRC, BrunoTC, WorkmanCJ, VignaliDAA. Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Semin Immunol 2019; 42 : 101305

[10] HuangX, ZhangX, LiE, ZhangG, WangX, TangT, BaiX, LiangT. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol 2020; 13( 1): 83

[11] GaoJ, WardJF, PettawayCA, ShiLZ, SubudhiSK, VenceLM, ZhaoH, ChenJ, ChenH, EfstathiouE, TroncosoP, AllisonJP, LogothetisCJ, WistubaII, SepulvedaMA, SunJ, WargoJ, BlandoJ, SharmaP. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 2017; 23( 5): 551– 555

[12] WillinghamSB, HotsonAN, MillerRA. Targeting the A2AR in cancer; early lessons from the clinic. Curr Opin Pharmacol 2020; 53 : 126– 133

[13] FongL, HotsonA, PowderlyJD, SznolM, HeistRS, ChoueiriTK, GeorgeS, HughesBGM, HellmannMD, ShepardDR, RiniBI, KummarS, WeiseAM, RieseMJ, MarkmanB, EmensLA, MahadevanD, LukeJJ, LaportG, BrodyJD, Hernandez-AyaL, BonomiP, GoldmanJW, BerimL, RenoufDJ, GoodwinRA, MunnekeB, HoPY, HsiehJ, McCafferyI, KweiL, WillinghamSB, MillerRA. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer. Cancer Discov 2020; 10( 1): 40– 53

[14] HanY, LiuD, LiL. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res 2020; 10( 3): 727– 742

[15] OhaegbulamKC, AssalA, Lazar-MolnarE, YaoY, ZangX. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 2015; 21( 1): 24– 33

[16] SchoenfeldAJ, HellmannMD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 2020; 37( 4): 443– 455

[17] WangY, MaR, LiuF, LeeSA, ZhangL. Modulation of gut microbiota: a novel paradigm of enhancing the efficacy of programmed death-1 and programmed death ligand-1 blockade therapy. Front Immunol 2018; 9 : 374

[18] DongH, ZhuG, TamadaK, ChenL. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999; 5( 12): 1365– 1369

[19] AkinleyeA, RasoolZ. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol 2019; 12( 1): 92

[20] ImSJ, HashimotoM, GernerMY, LeeJ, KissickHT, BurgerMC, ShanQ, HaleJS, LeeJ, NastiTH, SharpeAH, FreemanGJ, GermainRN, NakayaHI, XueHH, AhmedR. Defining CD8⁺ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016; 537( 7620): 417– 421

[21] YiM, YuS, QinS, LiuQ, XuH, ZhaoW, ChuQ, WuK. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J Hematol Oncol 2018; 11( 1): 47

[22] BuchbinderEI, DesaiA. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39( 1): 98– 106

[23] QureshiOS, ZhengY, NakamuraK, AttridgeK, ManzottiC, SchmidtEM, BakerJ, JefferyLE, KaurS, BriggsZ, HouTZ, FutterCE, AndersonG, WalkerLS, SansomDM. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011; 332( 6029): 600– 603

[24] RowshanravanB, HallidayN, SansomDM. CTLA-4: a moving target in immunotherapy. Blood 2018; 131( 1): 58– 67

[25] Yan CX, Zhang R, Wang NX. Immune-related adverse reactions with PD-1/PD-L1 mab. West China J Pharm Sci (Hua Xi Yao Xue Za Zhi) 2018; 33(3): 333−336 (in Chinese)

[26] YangH, ZhouC, YuanF, GuoL, YangL, ShiY, ZhangJ. Case report: severe immune-related cholestatic hepatitis and subsequent pneumonia after pembrolizumab therapy in a geriatic patient with metastic gastric cancer. Front Med (Lausanne) 2021; 8 : 719236

[27] JenkinsRW, BarbieDA, FlahertyKT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 2018; 118( 1): 9– 16

[28] BenfaremoD, ManfrediL, LuchettiMM, GabrielliA. Musculoskeletal and rheumatic diseases induced by immune checkpoint inhibitors: a review of the literature. Curr Drug Saf 2018; 13( 3): 150– 164

[29] Sun L, Liu Z, Zhang S. Adverse reaction and management of immune checkpoint inhibitor. J Med Postgra (Yi Xue Yan Jiu Sheng Xue Bao) 2019; 32(10): 1115−1120 (in Chinese)

[30] VilladolidJ, AminA. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res 2015; 4( 5): 560– 575

[31] ShahR, WittD, AsifT, MirFF. Ipilimumab as a cause of severe pan-colitis and colonic perforation. Cureus 2017; 9( 4): e1182

[32] KaramJD, NoelN, VoisinAL, LanoyE, MichotJM, LambotteO. Infectious complications in patients treated with immune checkpoint inhibitors. Eur J Cancer 2020; 141 : 137– 142

[33] DelCastillo M, RomeroFA, ArgüelloE, KyiC, PostowMA, Redelman-SidiG. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis 2016; 63( 11): 1490– 1493

[34] RossJA, KomodaK, PalS, DickterJ, SalgiaR, DadwalS. Infectious complications of immune checkpoint inhibitors in solid organ malignancies. Cancer Med 2022; 11( 1): 21– 27

[35] BoegeholzJ, BrueggenCS, PauliC, DimitriouF, HaralambievaE, DummerR, ManzMG, WidmerCC. Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect. BMC Cancer 2020; 20( 1): 300

[36] Guo M, Balaji A, Murray J, Reuss J, Steinke SM, Naidoo J. 237 Infectious complications in patients with non-small cell lung cancer treated with anti-PD (L) 1 immune checkpoint inhibitors. J Immunother Cancer 2021; 9(Suppl 2): A253

[37] FujitaK, KimYH, KanaiO, YoshidaH, MioT, HiraiT. Emerging concerns of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy. Respir Med 2019; 146 : 66– 70

[38] BrahmerJR, LacchettiC, SchneiderBJ, AtkinsMB, BrassilKJ, CaterinoJM, ChauI, ErnstoffMS, GardnerJM, GinexP, HallmeyerS, HolterChakrabarty J, LeighlNB, MammenJS, McDermottDF, NaingA, NastoupilLJ, PhillipsT, PorterLD, PuzanovI, ReichnerCA, SantomassoBD, SeigelC, SpiraA, Suarez-AlmazorME, WangY, WeberJS, WolchokJD, ThompsonJA; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36( 17): 1714– 1768

[39] Li GH, Huang HB, Yang M, Chen X, Liu ST, Zheng ZH. Guidelines for whole-course pharmaceutical care with immune checkpoint inhibitors (2019 Edition). Pharm Today (Jin Ri Yao Xue) 2020; 30(5): 289−306 (in Chinese)

[40] Yang MX, Yuan M, Tong JD, Yan XB. Role of antibiotics in tumor development and immunotherapy. J Int Oncol (Guo Ji Zhong Liu Xue Za Zhi) 2021; 48(1): 48−51 (in Chinese)

[41] CastelloA, RossiS, ToschiL, LopciE. Impact of antibiotic therapy and metabolic parameters in non-small cell lung cancer patients receiving checkpoint inhibitors. J Clin Med 2021; 10( 6): 1251

[42] Wang YH, ZhangRH. Progress in diagnosis and treatment of adverse reactions related to immune checkpoint inhibitors in advanced lung cancer. Zhejiang Med (Zhe Jiang Yi Xue) 2020; 42(12): 1227−1231 (in Chinese)

[43] FishmanJA, HoganJI, MausMV. Inflammatory and infectious syndromes associated with cancer immunotherapies. Clin Infect Dis 2019; 69( 6): 909– 920

[44] HuangXZ, GaoP, SongYX, XuY, SunJX, ChenXW, ZhaoJH, WangZN. Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients. OncoImmunology 2019; 8( 12): e1665973

[45] PinatoDJ, HowlettS, OttavianiD, UrusH, PatelA, MineoT, BrockC, PowerD, HatcherO, FalconerA, IngleM, BrownA, GujralD, PartridgeS, SarwarN, GonzalezM, BendleM, LewanskiC, Newsom-DavisT, AllaraE, BowerM. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 2019; 5( 12): 1774– 1778

[46] GalliG, TriulziT, ProtoC, SignorelliD, ImbimboM, PoggiM, FucàG, GanzinelliM, VitaliM, PalmieriD, TessariA, deBraud F, GarassinoMC, ColomboMP, LoRusso G. Association between antibiotic-immunotherapy exposure ratio and outcome in metastatic non small cell lung cancer. Lung Cancer 2019; 132 : 72– 78

[47] Tsikala-VafeaM, BelaniN, VieiraK, KhanH, FarmakiotisD. Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Int J Infect Dis 2021; 106 : 142– 154

[48] HakozakiT, OkumaY, OmoriM, HosomiY. Impact of prior antibiotic use on the efficacy of nivolumab for non-small cell lung cancer. Oncol Lett 2019; 17( 3): 2946– 2952

[49] Mata-MolanesJJ, SuredaGonzález M, ValenzuelaJiménez B, MartínezNavarro EM, BrugarolasMasllorens A. Cancer immunotherapy with cytokine-induced killer cells. Target Oncol 2017; 12( 3): 289– 299

[50] SethiV, KurtomS, TariqueM, LavaniaS, MalchiodiZ, HellmundL, ZhangL, SharmaU, GiriB, GargB, FerrantellaA, VickersSM, BanerjeeS, DawraR, RoyS, RamakrishnanS, SalujaA, DudejaV. Gut microbiota promotes tumor growth in mice by modulating immune response. Gastroenterology 2018; 155( 1): 33– 37.e6

[51] WeiMY, ShiS, LiangC, MengQC, HuaJ, ZhangYY, LiuJ, ZhangB, XuJ, YuXJ. The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer 2019; 18( 1): 97

[52] HillDA, HoffmannC, AbtMC, DuY, KobuleyD, KirnTJ, BushmanFD, ArtisD. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol 2010; 3( 2): 148– 158

[53] RoutyB, LeChatelier E, DerosaL, DuongCPM, AlouMT, DaillèreR, FluckigerA, MessaoudeneM, RauberC, RobertiMP, FidelleM, FlamentC, Poirier-ColameV, OpolonP, KleinC, IribarrenK, MondragónL, JacquelotN, QuB, FerrereG, ClémensonC, MezquitaL, MasipJR, NaltetC, BrosseauS, KaderbhaiC, RichardC, RizviH, LevenezF, GalleronN, QuinquisB, PonsN, RyffelB, Minard-ColinV, GoninP, SoriaJC, DeutschE, LoriotY, GhiringhelliF, ZalcmanG, GoldwasserF, EscudierB, HellmannMD, EggermontA, RaoultD, AlbigesL, KroemerG, ZitvogelL. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359( 6371): 91– 97

[54] AhmedJ, KumarA, ParikhK, AnwarA, KnollBM, PuccioC, ChunH, FanucchiM, LimSH. Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors. OncoImmunology 2018; 7( 11): e1507670

[55] Yin Y, Qiu XY, Zhao ZG, Zhang YH. Discussion on the effect of antibiotics on the effectiveness of PD-1/PD-L1 antibody immunotherapy. Pract Pharm Clin Remedies (Shi Yong Yao Wu Yu Lin Chuang) 2021; 24(3): 267−269 (in Chinese)

[56] SpakowiczD, HoydR, MuniakM, HusainM, BassettJS, WangL, TinocoG, PatelSH, BurkartJ, MiahA, LiM, JohnsA, GroganM, CarboneDP, VerschraegenCF, KendraKL, OttersonGA, LiL, PresleyCJ, OwenDH. Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications. BMC Cancer 2020; 20( 1): 383

[57] DerosaL, HellmannMD, SpazianoM, HalpennyD, FidelleM, RizviH, LongN, PlodkowskiAJ, ArbourKC, ChaftJE, RoucheJA, ZitvogelL, ZalcmanG, AlbigesL, EscudierB, RoutyB. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018; 29( 6): 1437– 1444

[58] SchettA, RothschildSI, Curioni-FontecedroA, KrähenbühlS, FrühM, SchmidS, DriessenC, JoergerM. Predictive impact of antibiotics in patients with advanced non small-cell lung cancer receiving immune checkpoint inhibitors: antibiotics immune checkpoint inhibitors in advanced NSCLC. Cancer Chemother Pharmacol 2020; 85( 1): 121– 131

[59] LangeK, BuergerM, StallmachA, BrunsT. Effects of antibiotics on gut microbiota. Dig Dis 2016; 34( 3): 260– 268

[60] JakobssonHE, JernbergC, AnderssonAF, Sjölund-KarlssonM, JanssonJK, EngstrandL. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One 2010; 5( 3): e9836

[61] YuY, ZhengP, GaoL, LiH, TaoP, WangD, DingF, ShiQ, ChenH. Effects of antibiotic use on outcomes in cancer patients treated using immune checkpoint inhibitors: a systematic review and meta-analysis. J Immunother 2021; 44( 2): 76– 85

[62] Iglesias-SantamaríaA. Impact of antibiotic use and other concomitant medications on the efficacy of immune checkpoint inhibitors in patients with advanced cancer. Clin Transl Oncol 2020; 22( 9): 1481– 1490

[63] TinsleyN, ZhouC, TanG, RackS, LoriganP, BlackhallF, KrebsM, CarterL, ThistlethwaiteF, GrahamD, CookN. Cumulative antibiotic use significantly decreases efficacy of checkpoint inhibitors in patients with advanced cancer. Oncologist 2020; 25( 1): 55– 63

[64] UrsellLK MetcalfJL ParfreyLW KnightR. Defining the human microbiome. Nutr Rev 2012; 70(Suppl 1): S38–S44

[65] BergG, RybakovaD, FischerD, CernavaT, VergèsMC, CharlesT, ChenX, CocolinL, EversoleK, CorralGH, KazouM, KinkelL, LangeL, LimaN, LoyA, MacklinJA, MaguinE, MauchlineT, McClureR, MitterB, RyanM, SarandI, SmidtH, SchelkleB, RoumeH, KiranGS, SelvinJ, SouzaRSC, vanOverbeek L, SinghBK, WagnerM, WalshA, SessitschA, SchloterM. Microbiome definition re-visited: old concepts and new challenges. Microbiome 2020; 8( 1): 103

[66] VelikovaT, KrastevB, LozenovS, GenchevaR, Peshevska-SekulovskaM, NikolaevG, PeruhovaM. Antibiotic-related changes in microbiome: the hidden villain behind colorectal carcinoma immunotherapy failure. Int J Mol Sci 2021; 22( 4): 1754

[67] AlexanderJL, WilsonID, TeareJ, MarchesiJR, NicholsonJK, KinrossJM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 2017; 14( 6): 356– 365

[68] Zhang BC, Peng M, Song QB. Relationship between gut microbiome and efficacy of immunotherapy. J Chin Oncol (Zhong Liu Xue Za Zhi) 2018; 24(11): 1056−1059 (in Chinese)

[69] SivanA, CorralesL, HubertN, WilliamsJB, Aquino-MichaelsK, EarleyZM, BenyaminFW, LeiYM, JabriB, AlegreML, ChangEB, GajewskiTF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350( 6264): 1084– 1089

[70] SwamiU, ZakhariaY, ZhangJ. Understanding microbiome effect on immune checkpoint inhibition in lung cancer: placing the puzzle pieces together. J Immunother 2018; 41( 8): 359– 360

[71] FrancinoMP. Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances. Front Microbiol 2016; 6 : 1543

[72] DethlefsenL RelmanDA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA 2011; 108(Suppl 1): 4554–4561

[73] YoonMY, YoonSS. Disruption of the gut ecosystem by antibiotics. Yonsei Med J 2018; 59( 1): 4– 12

[74] PinatoDJ, GramenitskayaD, AltmannDM, BoytonRJ, MullishBH, MarchesiJR, BowerM. Antibiotic therapy and outcome from immune-checkpoint inhibitors. J Immunother Cancer 2019; 7( 1): 287

[75] VétizouM, PittJM, DaillèreR, LepageP, WaldschmittN, FlamentC, RusakiewiczS, RoutyB, RobertiMP, DuongCP, Poirier-ColameV, RouxA, BecharefS, FormentiS, GoldenE, CordingS, EberlG, SchlitzerA, GinhouxF, ManiS, YamazakiT, JacquelotN, EnotDP, BérardM, NigouJ, OpolonP, EggermontA, WoertherPL, ChachatyE, ChaputN, RobertC, MateusC, KroemerG, RaoultD, BonecaIG, CarbonnelF, ChamaillardM, ZitvogelL. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350( 6264): 1079– 1084

[76] DubinK, CallahanMK, RenB, KhaninR, VialeA, LingL, NoD, GobourneA, LittmannE, HuttenhowerC, PamerEG, WolchokJD. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun 2016; 7( 1): 10391

[77] PushalkarS, HundeyinM, DaleyD, ZambirinisCP, KurzE, MishraA, MohanN, AykutB, UsykM, TorresLE, WerbaG, ZhangK, GuoY, LiQ, AkkadN, LallS, WadowskiB, GutierrezJ, Kochen RossiJA, HerzogJW, DiskinB, Torres-HernandezA, LeinwandJ, WangW, TaunkPS, SavadkarS, JanalM, SaxenaA, LiX, CohenD, SartorRB, SaxenaD, MillerG. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov 2018; 8( 4): 403– 416

[78] MatsonV, FesslerJ, BaoR, ChongsuwatT, ZhaY, AlegreML, LukeJJ, GajewskiTF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359( 6371): 104– 108

[79] DaillèreR, VétizouM, WaldschmittN, YamazakiT, IsnardC, Poirier-ColameV, DuongCPM, FlamentC, LepageP, RobertiMP, RoutyB, JacquelotN, ApetohL, BecharefS, RusakiewiczS, LangellaP, SokolH, KroemerG, EnotD, RouxA, EggermontA, TartourE, JohannesL, WoertherPL, ChachatyE, SoriaJC, GoldenE, FormentiS, PlebanskiM, MadondoM, RosenstielP, RaoultD, CattoirV, BonecaIG, ChamaillardM, ZitvogelL. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 2016; 45( 4): 931– 943

[80] DerosaL, RoutyB, FidelleM, IebbaV, AllaL, PasolliE, SegataN, DesnoyerA, PietrantonioF, FerrereG, FahrnerJE, LeChatellier E, PonsN, GalleronN, RoumeH, DuongCPM, MondragónL, IribarrenK, BonvaletM, TerrisseS, RauberC, GoubetAG, DaillèreR, LemaitreF, ReniA, CasuB, AlouMT, AlvesCosta Silva C, RaoultD, FizaziK, EscudierB, KroemerG, AlbigesL, ZitvogelL. Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients. Eur Urol 2020; 78( 2): 195– 206

[81] HammAK, WeirTL. Editorial on “Cancer and the microbiota” published in Science. Ann Transl Med 2015; 3( 13): 175

[82] WindTT, GacesaR, Vich VilaA, de HaanJJ, JalvingM, WeersmaRK, HospersGAP. Gut microbial species and metabolic pathways associated with response to treatment with immune checkpoint inhibitors in metastatic melanoma. Melanoma Res 2020; 30( 3): 235– 246

[83] GopalakrishnanV, SpencerCN, NeziL, ReubenA, AndrewsMC, KarpinetsTV, PrietoPA, VicenteD, HoffmanK, WeiSC, CogdillAP, ZhaoL, HudgensCW, HutchinsonDS, ManzoT, Petaccia de MacedoM, CotechiniT, KumarT, ChenWS, ReddySM, Szczepaniak SloaneR, Galloway-PenaJ, JiangH, ChenPL, ShpallEJ, RezvaniK, AlousiAM, ChemalyRF, ShelburneS, VenceLM, OkhuysenPC, JensenVB, SwennesAG, McAllisterF, Marcelo Riquelme SanchezE, ZhangY, Le ChatelierE, ZitvogelL, PonsN, Austin-BrenemanJL, HayduLE, BurtonEM, GardnerJM, SirmansE, HuJ, LazarAJ, TsujikawaT, DiabA, TawbiH, GlitzaIC, HwuWJ, PatelSP, WoodmanSE, AmariaRN, DaviesMA, GershenwaldJE, HwuP, LeeJE, ZhangJ, CoussensLM, CooperZA, FutrealPA, DanielCR, AjamiNJ, PetrosinoJF, TetzlaffMT, SharmaP, AllisonJP, JenqRR, WargoJA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359( 6371): 97– 103

[84] RezasoltaniS, YadegarA, Asadzadeh AghdaeiH, Reza ZaliM. Modulatory effects of gut microbiome in cancer immunotherapy: a novel paradigm for blockade of immune checkpoint inhibitors. Cancer Med 2021; 10( 3): 1141– 1154

[85] LiuX, ChenY, ZhangS, DongL. Gut microbiota-mediated immunomodulation in tumor. J Exp Clin Cancer Res 2021; 40( 1): 221

[86] GongJ, Chehrazi-RaffleA, Placencio-HickokV, GuanM, HendifarA, SalgiaR. The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies. Clin Transl Med 2019; 8( 1): 9

[87] ChaputN, LepageP, CoutzacC, SoularueE, Le RouxK, MonotC, BoselliL, RoutierE, CassardL, CollinsM, VaysseT, MartheyL, EggermontA, AsvatourianV, LanoyE, MateusC, RobertC, CarbonnelF. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017; 28( 6): 1368– 1379

[88] RoundJL, MazmanianSK. Inducible Foxp3⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA 2010; 107( 27): 12204– 12209

[89] Thiele OrbergE, FanH, TamAJ, DejeaCM, Destefano ShieldsCE, WuS, ChungL, FinardBB, WuX, FathiP, GangulyS, FuJ, PardollDM, SearsCL, HousseauF. The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis. Mucosal Immunol 2017; 10( 2): 421– 433

[90] SmithPM, HowittMR, PanikovN, MichaudM, GalliniCA, Bohlooly-YM, GlickmanJN, GarrettWS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013; 341( 6145): 569– 573

[91] XuX, LvJ, GuoF, LiJ, JiaY, JiangD, WangN, ZhangC, KongL, LiuY, ZhangY, LvJ, LiZ. Gut microbiome influences the efficacy of PD-1 antibody immunotherapy on MSS-type colorectal cancer via metabolic pathway. Front Microbiol 2020; 11 : 814

[92] LiuJ, GaoY, WangX, QianZ, ChenJ, HuangY, MengZ, LuX, DengG, LiuF, ZhangZ, LiH, ZhengX. Culture-positive spontaneous ascitic infection in patients with acute decompensated cirrhosis: multidrug-resistant pathogens and antibiotic strategies. Yonsei Med J 2020; 61( 2): 145– 153

[93] LeeEH, KimS, ChoiMS, YangH, ParkSM, OhHA, MoonKS, HanJS, KimYB, YoonS, OhJH. Gene networking in colistin-induced nephrotoxicity reveals an adverse outcome pathway triggered by proteotoxic stress. Int J Mol Med 2019; 43( 3): 1343– 1355

[94] ImdadA, NicholsonMR, Tanner-SmithEE, ZackularJP, Gomez-DuarteOG, BeaulieuDB, AcraS. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev 2018; 11 : CD012774

[95] KamadaN, SeoSU, ChenGY, NúñezG. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 2013; 13( 5): 321– 335

[96] PickardJM, ZengMY, CarusoR, NúñezG. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev 2017; 279( 1): 70– 89

[97] SchwartzDJ, RebeckON, DantasG. Complex interactions between the microbiome and cancer immune therapy. Crit Rev Clin Lab Sci 2019; 56( 8): 567– 585

[98] ChenD, WuJ, JinD, WangB, CaoH. Fecal microbiota transplantation in cancer management: current status and perspectives. Int J Cancer 2019; 145( 8): 2021– 2031

[99] BaruchEN, YoungsterI, Ben-BetzalelG, OrtenbergR, LahatA, KatzL, AdlerK, Dick-NeculaD, RaskinS, BlochN, RotinD, AnafiL, AviviC, MelnichenkoJ, Steinberg-SilmanY, MamtaniR, HaratiH, AsherN, Shapira-FrommerR, Brosh-NissimovT, EshetY, Ben-SimonS, ZivO, KhanMAW, AmitM, AjamiNJ, BarshackI, SchachterJ, WargoJA, KorenO, MarkelG, BoursiB. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2021; 371( 6529): 602– 609

[100] DavarD, DzutsevAK, McCullochJA, RodriguesRR, ChauvinJM, MorrisonRM, DeblasioRN, MennaC, DingQ, PaglianoO, ZidiB, ZhangS, BadgerJH, VetizouM, ColeAM, FernandesMR, PrescottS, CostaRGF, BalajiAK, MorgunA, Vujkovic-CvijinI, WangH, BorhaniAA, SchwartzMB, DubnerHM, ErnstSJ, RoseA, NajjarYG, BelkaidY, KirkwoodJM, TrinchieriG, ZarourHM. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021; 371( 6529): 595– 602

[101] DoronS SnydmanDR. Risk and safety of probiotics. Clin Infect Dis 2015; 60(Suppl 2): S129–S134

[102] PandeyKR, NaikSR, VakilBV. Probiotics, prebiotics and synbiotics—a review. J Food Sci Technol 2015; 52( 12): 7577– 7587

[103] GibsonGR, RoberfroidMB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995; 125( 6): 1401– 1412

[104] HuY, Le LeuRK, ChristophersenCT, SomashekarR, ConlonMA, MengXQ, WinterJM, WoodmanRJ, McKinnonR, YoungGP. Manipulation of the gut microbiota using resistant starch is associated with protection against colitis-associated colorectal cancer in rats. Carcinogenesis 2016; 37( 4): 366– 375

[105] LiW, DengY, ChuQ, ZhangP. Gut microbiome and cancer immunotherapy. Cancer Lett 2019; 447 : 41– 47

[106] BotticelliA, ZizzariI, MazzucaF, AsciertoPA, PutignaniL, MarchettiL, NapoletanoC, NutiM, MarchettiP. Cross-talk between microbiota and immune fitness to steer and control response to anti PD-1/PDL-1 treatment. Oncotarget 2017; 8( 5): 8890– 8899

[107] LiY, ZhaoR, ChengK, ZhangK, WangY, ZhangY, LiY, LiuG, XuJ, XuJ, AndersonGJ, ShiJ, RenL, ZhaoX, NieG. Bacterial outer membrane vesicles presenting programmed death 1 for improved cancer immunotherapy via immune activation and checkpoint inhibition. ACS Nano 2020; 14( 12): 16698– 16711

[108] HuangJ, LiuD, WangY, LiuL, LiJ, YuanJ, JiangZ, JiangZ, HsiaoWW, LiuH, KhanI, XieY, WuJ, XieY, ZhangY, FuY, LiaoJ, WangW, LaiH, ShiA, CaiJ, LuoL, LiR, YaoX, FanX, WuQ, LiuZ, YanP, LuJ, YangM, WangL, CaoY, WeiH, LeungEL. Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy. Gut 2022; 71( 4): 734– 745

[109] LvJ, JiaY, LiJ, KuaiW, LiY, GuoF, XuX, ZhaoZ, LvJ, LiZ. Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment. Cell Death Dis 2019; 10( 6): 415

[110] ZhenH QianX FuX Chen Z ZhangA ShiL. Regulation of Shaoyao Ruangan mixture on intestinal flora in mice with primary liver cancer. Integr Cancer Ther 2019; 18: 1534735419843178

[111] McFaddenRM, LarmonierCB, ShehabKW, Midura-KielaM, RamalingamR, HarrisonCA, BesselsenDG, ChaseJH, CaporasoJG, JobinC, GhishanFK, KielaPR. The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention. Inflamm Bowel Dis 2015; 21( 11): 2483– 2494

[112] ConlonMA, BirdAR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 2014; 7( 1): 17– 44

[113] MehtaRS, NishiharaR, CaoY, SongM, MimaK, QianZR, NowakJA, KosumiK, HamadaT, MasugiY, BullmanS, DrewDA, KosticAD, FungTT, GarrettWS, HuttenhowerC, WuK, MeyerhardtJA, ZhangX, WillettWC, GiovannucciEL, FuchsCS, ChanAT, OginoS. Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol 2017; 3( 7): 921– 927

[114] De FilippoC, CavalieriD, Di PaolaM, RamazzottiM, PoulletJB, MassartS, ColliniS, PieracciniG, LionettiP. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010; 107( 33): 14691– 14696

[115] WeiW, SunW, YuS, YangY, AiL. Butyrate production from high-fiber diet protects against lymphoma tumor. Leuk Lymphoma 2016; 57( 10): 2401– 2408

[116] FengJ, YangH, ZhangY, WeiH, ZhuZ, ZhuB, YangM, CaoW, WangL, WuZ. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 2017; 36( 42): 5829– 5839

[117] SethP, CsizmadiaE, HedblomA, VuerichM, XieH, LiM, LonghiMS, WegielB. Deletion of lactate dehydrogenase-A in myeloid cells triggers antitumor immunity. Cancer Res 2017; 77( 13): 3632– 3643

[118] PoroykoVA, CarrerasA, KhalyfaA, KhalyfaAA, LeoneV, PerisE, AlmendrosI, Gileles-HillelA, QiaoZ, HubertN, FarréR, ChangEB, GozalD. Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice. Sci Rep 2016; 6( 1): 35405

[119] WangY, KuangZ, YuX, RuhnKA, KuboM, HooperLV. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 2017; 357( 6354): 912– 916

[120] WangJ, YangHR, WangDJ, WangXX. Association between the gut microbiota and patient responses to cancer immune checkpoint inhibitors. Oncol Lett 2020; 20( 6): 342

[121] LeeKA, ShawHM, BatailleV, NathanP, SpectorTD. Role of the gut microbiome for cancer patients receiving immunotherapy: dietary and treatment implications. Eur J Cancer 2020; 138 : 149– 155

[122] ZhangJ, DaiZ, YanC, ZhangW, WangD, TangD. A new biological triangle in cancer: intestinal microbiota, immune checkpoint inhibitors and antibiotics. Clin Transl Oncol 2021; 23( 12): 2415– 2430

[123] PatelP, PoudelA, KafleS, Thapa MagarM, CancarevicI. Influence of microbiome and antibiotics on the efficacy of immune checkpoint inhibitors. Cureus 2021; 13( 8): e16829

[124] QuJ, JiangM, WangL, ZhaoD, QinK, WangY, TaoJ, ZhangX. Mechanism and potential predictive biomarkers of immune checkpoint inhibitors in NSCLC. Biomed Pharmacother 2020; 127 : 109996

Acknowledgements

This study was supported by Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2020L03) and Beijing Municipal Science & Technology Commission (No. Z181100001618003).

Compliance with ethics guidelines

Yingying Li, Shiyuan Wang, Mengmeng Lin, Chunying Hou, Chunyu Li, and Guohui Li declare no conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2022 Higher Education Press