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. 2018 Sep 30;6(3):e84. doi: 10.15190/d.2018.4

Gut Microbiome and the Response to Immunotherapy in Cancer

Andreea Lucia Stancu 1,*
PMCID: PMC7086073  PMID: 32309602

Abstract

Recent studies indicate that the composition of gut bacteria can influence the effectiveness of certain cancer immunotherapy drugs and that modulating the gut microbiome may expand the pool of patients benefiting from cancer immunotherapies. Checkpoint blockade therapy has been effective on several types of malignancies (e.g. melanoma, lung cancer, kidney cancer). However, the number of patients that do not respond, or only partially respond, to cancer immunotherapy is high. Recently, several human and mouse studies have shown that gut microbiome may be a significant determinant of the response to cancer immunotherapy. This review focuses on the recent advances in our understanding of the interaction between human gut microbiome and response to immunotherapy in cancer. The gut microbiome may serve as a theranostic biomarker, by acting both as a useful prognostic biomarker and a target in cancer therapy.

Keywords: Cancer, immunotherapy, microbiome, response to therapy, PD-1, PD-L1.

1. Introduction

Immune checkpoint therapies have enabled a breakthrough in the therapy of the hematologic and solid metastatic malignancies1-4. Administration of monoclonal antibodies unleashes a T lymphocyte-mediated immune response by inhibiting the interaction of T-cell suppressing receptors with their corresponding ligand on tumor cells2. In particular, immune checkpoint inhibitors that target programmed cell death protein 1 (PD-1) and its ligand PD-L1, have to date been approved by the U.S. Food and Drug Administration (FDA) for the use in the treatment of patients with 10 distinct cancer types5.

In anti-tumor therapy, specific CD8+ cytotoxic T lymphocytes (CTL) are generated, recognize specific tumor antigens and induce caspase-dependent cell death in tumor cells6,7. However, tumor cells can utilize a wide range of immune escape strategies. An important escaping mechanism is the one exploiting the PD-1 - PD-L1 interaction, in which CTLs are inhibited through PD-1 receptor on their surface by the PD-L1 ligand, found on tumor or other cells. For example, it was shown that PD-L1 expressing cancer cells induce caspase-dependent cell death of co-cultured activated CTLs and an anti-human PD-L1 monoclonal antibody can block this interaction and its effects. Other studies replicated these results in mouse models6,8-10. Although most normal tissues do not express detectable PD-L1 levels on their cellular surface, PD-L1 is highly expressed in tumor cells and some immune/non-immune cells in tumor environment11-19. Moreover, certain cytokines, such as TNF-alpha, IL-4, IL-10 and IFN-gamma play an important role in increasing the expression of PD-L16,20-22. PD-1 interaction with its PD-L1 ligand leads to suppression of the effector T cells, by inducing T cell apoptosis, anergy and/or exhaustion6,20,23. Moreover, the phagocytic activity of macrophages against tumor cells can also be suppressed by PD-1 - PD-L1 interaction6,24. All these results and others not mentioned here led to a significant number of studies focusing on disrupting this interaction for cancer treatment6.

Many clinical trials are now underway, testing monoclonal antibodies against PD-L1 or PD-1, as a cancer immunotherapy strategy for a variety of malignancies. These treatments may work both by disrupting the immunological-related pathways, but also by disrupting intracellular tumor signaling pathways25. Currently, there are at least 5 monoclonal antibodies targeting PD-1 or PD-L1 approved by the FDA as cancer immunotherapy6.

Responses to immunotherapy targeting PD-1 or PD-L1 are often heterogeneous and not durable. Primary resistance, observed in the majority of the cases, has been associated with low mutational burden, poor intrinsic antigenicity of tumor cells, defective antigen presentation during the priming phase, functional exhaustion of tumor-infiltrating lymphocytes and local immunosuppression by extracellular metabolites6,8-11,26,27. Thus, different approaches to optimize the efficacy of cancer immunotherapy are in high demand.

Recent studies suggest that modulation of the gut microbiota is a promising approach. Several human and mouse studies have shown that gut microbiome may be a significant determinant of the response to cancer immunotherapy6,15,17-19,28-35. The number of studies investigating microbiome’s relation with the cancer immunotherapy is growing exponentially (Figure 1). Thus, we and others think that the gut microbiome may serve as a theranostic biomarker, by acting both as a useful prognostic biomarker and a target in cancer therapy.

Figure 1. Figure 1. Exponential growth of the number of articles published between 2003-2018 related to the “cancer immunotherapy” and “microbioma”.

Figure 1

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This graph is based on the PubMed publications data. Data for 2018 is collected for January-September 2018.

2. Role of microbiota in immune checkpoint therapy

Stem cell transplant can be considered one of the first immunotherapy strategies for cancer treatment (e.g. transplant for leukemia treatment). In recent years, an exponential number of studies30,35 initiated new immunotherapeutic approaches, which were initially demonstrated in mouse models with many of them (e.g. anti-PD-1 or anti-PD-L1 treatments) being validated in humans30,35.

Although not considered immunotherapy, the response to the standard chemotherapy treatment is at least in part based on the activation of the immune system. Over 10 years ago, Paulos et al. observed that antibiotics inhibited anti-cancer activity in melanoma, a murine model of adoptive cell therapy, while translocation of bacteria from the gut helped by initiating a TLR4-dependent immune response36. Subsequent studies confirmed these findings by using platinum and cyclophosphamide-based therapy34,37.

The role of gut microbiome as a response to the immune checkpoint blockade was similarly initiated in mouse models, showing that gut bacteria influences the response to cancer immunotherapy (targeting CTLA-4 and PD-1)30,35. Many of the patients do not respond to the treatment with immune checkpoint inhibitors. Interestingly, oral administration of certain types of Bacteroides (Bacteroides fragilis together with Burkholderia cepacia or Bacteroides thetaiotaomicron) stimulated anti-CTLA-4 immunotherapy35. Many other studies were subsequently published showing that gut bacteria is associated and/or modulates the resistance to immunotherapy, such as anti-PD-1 or anti-PD-L1 treatments6,15,17-19,28-34.

Of note, microbiota can be transplanted to other mice and the beneficial effects are transmitted to the new host. Supplementation with a probiotic orally administered containing Bifidobacterium re-sensitized the tumors to anti-PD-L1 therapy in mice, by promoting DC maturation and an increase in anti-tumor CD8+ CTL activity33.

In the past two years, a significant number of bacteria were determined to modulate anti-PD-1 or anti-PD-L1 therapy in a wide range of malignancies, such as melanoma, lung cancer, kidney cancer. A summary of the most important bacterial candidates is presented in Table 1. Notably, few of them (such as Bifidobacterium) were confirmed in multiple studies to be present in higher abundance in responders to immunotherapy and that mice that received the bacteria species Bifidobacterium have a marked increase in anti-tumor T cell responses30.

Table 1. Examples of bacteria as potential modulators of the anti-PD-1 immunotherapy in cancer (their modulatory mechanisms and effects have to be further investigated).

Ref. – Reference(s).

Bacteria (Gut) Effect Ref.
Ruminococcaceae family Higher abundance in responders to anti-PD-1 therapy (melanoma); also, higher diversity of bacteria observed 33
Faecalibacterium genus Higher abundance in responders to anti-PD-1 therapy (melanoma); also, higher diversity of bacteria observed 33
Bifidobacterium longum and Bifidobacterium adolescentis Higher abundance in responders to anti-PD-1 therapy (metastatic melanoma) 29,30
Collinsella aerofaciens Higher abundance in responders to anti-PD-1 therapy (metastatic melanoma) 29
Enterococcus faecium Higher abundance in responders to anti-PD-1 therapy (metastatic melanoma) 29
Klebsiela pneumoniae Higher abundance in responders to anti-PD-1 therapy (metastatic melanoma) 29
Veillonella parvula Higher abundance in responders to anti-PD-1 therapy (metastatic melanoma) 29
Parabacteroides merdae Higher abundance in responders to anti-PD-1 therapy (metastatic melanoma) 29
Lactobacillus sp. Higher abundance in responders to anti-PD-1 therapy (metastatic melanoma) 29
Akkermansia muciniphila Higher abundance in responders to anti-PD-1 therapy (lung and kidney cancers); exposure to antibiotics decreases response 31
Ruminococcus obeum Higher abundance in non-responders to anti-PD-1 therapy (metastatic melanoma) 29
Roseburia intestinalis Higher abundance in non-responders to anti-PD-1 therapy (metastatic melanoma) 29
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The mechanisms through which some bacteria enhance anti-tumor immunotherapy are not yet clearly defined. Recent studies suggest that tumor antigens are similar to those found on infectious pathogens38,39.Other studies suggest that the metabolic effects are involved or that the microbiota determines “the tonus of the immune reseponse”39,40.Thus, further studies are required to elucidate these mechanistic aspects.

3. Microbial intervention as adjuvant therapy for immunotherapy in cancer

Considering the exponential increase of the scientific community’s interest and the exciting already published studies, the involvement and potential modulation of gut microbiota may represent an important adjuvant in cancer immunotherapy in the near future.

Although the exact molecular mechanisms of the microbiota interactions with cancer therapies are not completely understood, several clinical trials are already ongoing (Table 2). For example, at least 3 observational studies (NCT02960282, NCT03643289, NCT0368834) and one interventional (NCT03686202) are now recruiting patients (Table 2). In the first mentioned trial, the gut microbiome will be investigated in the fecal samples from patients with metastatic cancer undergoing chemotherapy and immunotherapy. In a second clinical trial, the gut microbiome diversity will be assessed with metagenome sequencing before and after immunotherapy, in order to predict the response to immunotherapy for melanoma. The third trial will investigate the nasal, oral and fecal microbiome, and correlate the data with treatment response and toxicities of immunotherapy, in lung cancer and other malignancies. The NCT03686202 interventional clinical trial (phase 1) will assess the safety, tolerability and engraftment of Microbial Ecosystem Therapeutics (MET-4) strains when given in combination with immunotherapy, in solid tumors. Other clinical trials aim investigating the dietary, other lifestyle or environmental factors in relation to cancer therapy, or the direct use of live genetically modified bacteria as an immunotherapy treatment (Table 2).

Table 2. Clinical trials evaluating microbial role/intervention as immunotherapy modulator in cancer.

(based on ClinicalTrials.gov, website maintained by the National Library of Medicine, at the US National Institutes of Health (NIH)

ClinicalTrials.gov Identifier Name of the study Conditions Comments Status
NCT02960282 Gut Microbiome in Fecal Samples from Patients with Metastatic Cancer Undergoing Chemotherapy or Immunotherapy Colorectal Cancer (stage 4) Observational study; Biospecimen Collection; Laboratory Biomarker Analysis Recruiting
NCT03643289 Predicting Response to Immunotherapy for Melanoma with Gut Microbiome & Metabolomics Melanoma (stage 4) Observational study; Assess the gut microbiome diversity with metagenome sequencing before and after immunotherapy Recruiting
NCT03688347 Microbiome in Lung Cancer and other Malignancies Lung cancer, other cancers Observational study; Assess the nasal, oral and fecal microbiome, and correlate the data with treatment response and toxicities of immunotherapy Recruiting
NCT03686202 Feasibility Study of Microbial Ecosystem Therapeutics (MET-4) to Evaluate Effects of Fecal Microbiome in Patients on Immunotherapy Solid tumors Interventional (Phase 1); Assess the safety, tolerability and engraftment of Microbial Ecosystem Therapeutics (MET-4) strains when given in combination with immunotherapy Recruiting
NCT02592967 Safety & Immunogenicity of JNJ-64041757, Live-attenuated Double-deleted Listeria Immunotherapy, in Subjects with Non Small Cell Lung Cancer Non-small cell lung cancer (NSCLC) (stages 3B and 4) Interventional (Phase 1); Assess the JNJ-64041757, a live attenuated double deleted (LADD) Listeria monocytogenes as single immunotherapy Active
NCT02625857 Safety & Immunogenicity of JNJ-64041809, a Live Attenuated Double-deleted Listeria Immunotherapy, in Participants with Metastatic Castration-resistant Prostate Cancer Prostate cancer, castration-resistant Interventional (Phase 1); Assess the JNJ-64041809, a live attenuated double deleted (LADD) Listeria monocytogenes as single immunotherapy Completed
NCT02843425 The Beans to Enrich the Gut Microbiome vs. Obesity's Negative Effects (BE GONE) Trial Colorectal cancer Prevention Interventional; Assess the fiber supplementation -induced shift in bacterial populations, through the addition of a half cup of beans/day into the normal diets of cancer patients Recruiting
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Diet may serve as an important tool for modulating the microbiome in relation to the anti-cancer immunotherapy. The main function of microbiota is to help in food digestion and producing valuable factors (e.g. vitamin K), that the host can’t produce itself41. Dietary variation modifies the microbiome composition. Several proof-of-concept studies demonstrated how dietary modulation can be employed as a strategy to influence the gut microbiome and immune health42,43. Dietary fibers have been previously established to have an important influence on the gut microbiome composition44. The NCT02843425 (“BE GONE”) interventional clinical trial assesses the fiber supplementation-induced shift in bacterial populations, through the addition of a half cup of beans/day into the normal diets of cancer patients (colorectal cancer). Additional clinical trials investigating the role of dietary supplements and other factors on the microbiota/microbiome in the context of cancer are underway (NCT02079662, NCT03072641, NCT02928523, NCT01895530, NCT03353402, NCT03358511)33. Although, all these studies are just starting, they will provide critical information on how diet, lifestyle and environmental factors modulate the gut microbiome, provide new prognostic biomarkers and modulate the patient outcome.

4. Future directions

In the very recent few years, we have gained significant insights into the role of gut microbiome in cancer therapy, with a special focus on immunotherapy. The number of published studies is growing exponentially, and the first clinical trials are now ongoing. However, the exact mechanisms, involved bacteria and utility in various types of malignancies remain to be further investigated and understood.

In order to efficiently tackle these objectives, one has to use the optimal methods available. For example, selection of the sequencing methods for the microbiome and reference databases is very important33. Since reproducibility is often brought into question, it is important to properly set-up and execute these studies45.

Further investigations should determine the bacterial combination pools needed to facilitate the response to cancer immunotherapy in different types of malignancies and how we can develop or induce the development of such combinations. The outcome should be carefully investigated in clinical trials. Moreover, the role of other influencers, such as medications (drug treatments for other conditions, antibiotics, probiotics etc), diet, metabolic changes (e.g. exercise) and other internal conditions (e.g. mental health) and external factors have to be thoroughly investigated.

Taking advantage of the prognostic and modulatory role of the microbiome in cancer immunotherapy in particular, and cancer therapy in general, to enhance the anti-tumor immunity and immune surveillance, may be one of the dominant strategies in cancer therapy in the future.

Footnotes

Conflict of interests: The authors declare no conflicts of interest.

Abbreviations

Programmed Cell Death Protein 1 (PD-1); Food and Drug Administration (FDA); cytotoxic T cell (CTL); cytotoxic T lymphocyte antigen 4 (CTLA-4); Microbial Ecosystem Therapeutics (MET-4); US National Institutes of Health (NIH).

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References

  • 1.Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. Robert Caroline, Thomas Luc, Bondarenko Igor, O'Day Steven, Weber Jeffrey, Garbe Claus, Lebbe Celeste, Baurain Jean-François, Testori Alessandro, Grob Jean-Jacques, Davidson Neville, Richards Jon, Maio Michele, Hauschild Axel, Miller Wilson H., Gascon Pere, Lotem Michal, Harmankaya Kaan, Ibrahim Ramy, Francis Stephen, Chen Tai-Tsang, Humphrey Rachel, Hoos Axel, Wolchok Jedd D. New England Journal of Medicine. 2011;364(26):2517-2526. doi: 10.1056/NEJMoa1104621. [DOI] [PubMed] [Google Scholar]
  • 2.Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. Ribas Antoni, Hamid Omid, Daud Adil, Hodi F. Stephen, Wolchok Jedd D., Kefford Richard, Joshua Anthony M., Patnaik Amita, Hwu Wen-Jen, Weber Jeffrey S., Gangadhar Tara C., Hersey Peter, Dronca Roxana, Joseph Richard W., Zarour Hassane, Chmielowski Bartosz, Lawrence Donald P., Algazi Alain, Rizvi Naiyer A., Hoffner Brianna, Mateus Christine, Gergich Kevin, Lindia Jill A., Giannotti Maxine, Li Xiaoyun Nicole, Ebbinghaus Scot, Kang S. Peter, Robert Caroline. JAMA. 2016;315(15):1600. doi: 10.1001/jama.2016.4059. [DOI] [PubMed] [Google Scholar]
  • 3.Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. Borghaei Hossein, Paz-Ares Luis, Horn Leora, Spigel David R., Steins Martin, Ready Neal E., Chow Laura Q., Vokes Everett E., Felip Enriqueta, Holgado Esther, Barlesi Fabrice, Kohlhäufl Martin, Arrieta Oscar, Burgio Marco Angelo, Fayette Jérôme, Lena Hervé, Poddubskaya Elena, Gerber David E., Gettinger Scott N., Rudin Charles M., Rizvi Naiyer, Crinò Lucio, Blumenschein George R., Antonia Scott J., Dorange Cécile, Harbison Christopher T., Graf Finckenstein Friedrich, Brahmer Julie R. New England Journal of Medicine. 2015;373(17):1627-1639. doi: 10.1056/NEJMoa1507643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. Topalian Suzanne L., Hodi F. Stephen, Brahmer Julie R., Gettinger Scott N., Smith David C., McDermott David F., Powderly John D., Carvajal Richard D., Sosman Jeffrey A., Atkins Michael B., Leming Philip D., Spigel David R., Antonia Scott J., Horn Leora, Drake Charles G., Pardoll Drew M., Chen Lieping, Sharfman William H., Anders Robert A., Taube Janis M., McMiller Tracee L., Xu Haiying, Korman Alan J., Jure-Kunkel Maria, Agrawal Shruti, McDonald Daniel, Kollia Georgia D., Gupta Ashok, Wigginton Jon M., Sznol Mario. New England Journal of Medicine. 2012;366(26):2443-2454. doi: 10.1056/NEJMoa1200690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Sharma Padmanee, Hu-Lieskovan Siwen, Wargo Jennifer A., Ribas Antoni. Cell. 2017;168(4):707-723. doi: 10.1016/j.cell.2017.01.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Modulation of Gut Microbiota: A Novel Paradigm of Enhancing the Efficacy of Programmed Death-1 and Programmed Death Ligand-1 Blockade Therapy. Wang Yiming, Ma Rena, Liu Fang, Lee Seul A., Zhang Li. Frontiers in Immunology. 2018;9 doi: 10.3389/fimmu.2018.00374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Relapse or Eradication of Cancer Is Predicted by Peptide-Major Histocompatibility Complex Affinity. Engels Boris, Engelhard Victor H., Sidney John, Sette Alessandro, Binder David C., Liu Rebecca B., Kranz David M., Meredith Stephen C., Rowley Donald A., Schreiber Hans. Cancer Cell. 2013;23(4):516-526. doi: 10.1016/j.ccr.2013.03.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Iwai Y., Ishida M., Tanaka Y., Okazaki T., Honjo T., Minato N. Proceedings of the National Academy of Sciences. 2002;99(19):12293-12297. doi: 10.1073/pnas.192461099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+T Cells. Blank Christian, Brown Ian, Peterson Amy C., Spiotto Mike, Iwai Yoshiko, Honjo Tasuku, Gajewski Thomas F. Cancer Research. 2004;64(3):1140-1145. doi: 10.1158/0008-5472.can-03-3259. [DOI] [PubMed] [Google Scholar]
  • 10.Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Hirano Fumiya, Kaneko Katsumi, Tamura Hideto, Dong Haidong, Wang Shengdian, Ichikawa Masao, Rietz Cecilia, Flies Dallas B, Lau Julie S, Zhu Gefeng, Tamada Koji, Chen Lieping. Cancer research. 2005;65(3):1089–96. [PubMed] [Google Scholar]
  • 11.Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade. Johnson D. B., Frampton G. M., Rioth M. J., Yusko E., Xu Y., Guo X., Ennis R. C., Fabrizio D., Chalmers Z. R., Greenbowe J., Ali S. M., Balasubramanian S., Sun J. X., He Y., Frederick D. T., Puzanov I., Balko J. M., Cates J. M., Ross J. S., Sanders C., Robins H., Shyr Y., Miller V. A., Stephens P. J., Sullivan R. J., Sosman J. A., Lovly C. M. Cancer Immunology Research. 2016;4(11):959-967. doi: 10.1158/2326-6066.CIR-16-0143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.A human gut microbial gene catalogue established by metagenomic sequencing. Qin Junjie, Li Ruiqiang, Raes Jeroen, Arumugam Manimozhiyan, Burgdorf Kristoffer Solvsten, Manichanh Chaysavanh, Nielsen Trine, Pons Nicolas, Levenez Florence, Yamada Takuji, Mende Daniel R, Li Junhua, Xu Junming, Li Shaochuan, Li Dongfang, Cao Jianjun, Wang Bo, Liang Huiqing, Zheng Huisong, Xie Yinlong, Tap Julien, Lepage Patricia, Bertalan Marcelo, Batto Jean-Michel, Hansen Torben, Le Paslier Denis, Linneberg Allan, Nielsen H Bjørn, Pelletier Eric, Renault Pierre, Sicheritz-Ponten Thomas, Turner Keith, Zhu Hongmei, Yu Chang, Li Shengting, Jian Min, Zhou Yan, Li Yingrui, Zhang Xiuqing, Li Songgang, Qin Nan, Yang Huanming, Wang Jian, Brunak Søren, Doré Joel, Guarner Francisco, Kristiansen Karsten, Pedersen Oluf, Parkhill Julian, Weissenbach Jean, Bork Peer, Ehrlich S Dusko, Wang Jun. Nature. 2010;464(7285):59–65. doi: 10.1038/nature08821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Taur Ying, Jenq Robert R., Perales Miguel-Angel, Littmann Eric R., Morjaria Sejal, Ling Lilan, No Daniel, Gobourne Asia, Viale Agnes, Dahi Parastoo B., Ponce Doris M., Barker Juliet N., Giralt Sergio, van den Brink Marcel, Pamer Eric G. Blood. 2014;124(7):1174-1182. doi: 10.1182/blood-2014-02-554725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.'Final common pathway' of human cancer immunotherapy: targeting random somatic mutations. Tran Eric, Robbins Paul F, Rosenberg Steven A. Nature Immunology. 2017;18(3):255-262. doi: 10.1038/ni.3682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Microbial growth dynamics and human disease. Segre J. A. Science. 2015;349(6252):1058-1059. doi: 10.1126/science.aad0781. [DOI] [PubMed] [Google Scholar]
  • 16.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Rizvi Naiyer A, Hellmann Matthew D, Snyder Alexandra, Kvistborg Pia, Makarov Vladimir, Havel Jonathan J, Lee William, Yuan Jianda, Wong Phillip, Ho Teresa S, Miller Martin L, Rekhtman Natasha, Moreira Andre L, Ibrahim Fawzia, Bruggeman Cameron, Gasmi Billel, Zappasodi Roberta, Maeda Yuka, Sander Chris, Garon Edward B, Merghoub Taha, Wolchok Jedd D, Schumacher Ton N, Chan Timothy A. Science (New York, N.Y.) 2015;348(6230):124–8. doi: 10.1126/science.aaa1348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Diet Drives Convergence in Gut Microbiome Functions Across Mammalian Phylogeny and Within Humans. Muegge B. D., Kuczynski J., Knights D., Clemente J. C., Gonzalez A., Fontana L., Henrissat B., Knight R., Gordon J. I. Science. 2011;332(6032):970-974. doi: 10.1126/science.1198719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207-214. doi: 10.1038/nature11234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Diet-Induced Obesity Is Linked to Marked but Reversible Alterations in the Mouse Distal Gut Microbiome. Turnbaugh Peter J., Bäckhed Fredrik, Fulton Lucinda, Gordon Jeffrey I. Cell Host & Microbe. 2008;3(4):213-223. doi: 10.1016/j.chom.2008.02.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Dong Haidong, Zhu Gefeng, Tamada Koji, Chen Lieping. Nature Medicine. 1999;5(12):1365-1369. doi: 10.1038/70932. [DOI] [PubMed] [Google Scholar]
  • 21.B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function. Tamura Hideto, Dong Haidong, Zhu Gefeng, Sica Gabriel L., Flies Dallas B., Tamada Koji, Chen Lieping. Blood. 2001;97(6):1809-1816. doi: 10.1182/blood.v97.6.1809. [DOI] [PubMed] [Google Scholar]
  • 22.Interferon-γ and tumor necrosis factor-α induce an immunoinhibitory molecule, B7-H1, via nuclear factor-κB activation in blasts in myelodysplastic syndromes. Kondo Asaka, Yamashita Taishi, Tamura Hideto, Zhao Wanhong, Tsuji Takashi, Shimizu Masumi, Shinya Eiji, Takahashi Hidemi, Tamada Koji, Chen Lieping, Dan Kazuo, Ogata Kiyoyuki. Blood. 2010;116(7):1124-1131. doi: 10.1182/blood-2009-12-255125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1. Ghiotto M., Gauthier L., Serriari N., Pastor S., Truneh A., Nunes J. A., Olive D. International Immunology. 2010;22(8):651-660. doi: 10.1093/intimm/dxq049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Gordon Sydney R., Maute Roy L., Dulken Ben W., Hutter Gregor, George Benson M., McCracken Melissa N., Gupta Rohit, Tsai Jonathan M., Sinha Rahul, Corey Daniel, Ring Aaron M., Connolly Andrew J., Weissman Irving L. Nature. 2017;545(7655):495-499. doi: 10.1038/nature22396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.PD1 signal transduction pathways in T cells. Arasanz Hugo, Gato-Cañas Maria, Zuazo Miren, Ibañez-Vea Maria, Breckpot Karine, Kochan Grazyna, Escors David. Oncotarget. 2017;8(31) doi: 10.18632/oncotarget.17232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Spranger Stefani, Bao Riyue, Gajewski Thomas F. Nature. 2015;523(7559):231-235. doi: 10.1038/nature14404. [DOI] [PubMed] [Google Scholar]
  • 27.Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Koyama Shohei, Akbay Esra A., Li Yvonne Y., Herter-Sprie Grit S., Buczkowski Kevin A., Richards William G., Gandhi Leena, Redig Amanda J., Rodig Scott J., Asahina Hajime, Jones Robert E., Kulkarni Meghana M., Kuraguchi Mari, Palakurthi Sangeetha, Fecci Peter E., Johnson Bruce E., Janne Pasi A., Engelman Jeffrey A., Gangadharan Sidharta P., Costa Daniel B., Freeman Gordon J., Bueno Raphael, Hodi F. Stephen, Dranoff Glenn, Wong Kwok-Kin, Hammerman Peter S. Nature Communications. 2016;7(1) doi: 10.1038/ncomms10501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Gopalakrishnan V, Spencer C N, Nezi L, Reuben A, Andrews M C, Karpinets T V, Prieto P A, Vicente D, Hoffman K, Wei S C, Cogdill A P, Zhao L, Hudgens C W, Hutchinson D S, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen W S, Reddy S M, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen P L, Shpall E J, Rezvani K, Alousi A M, Chemaly R F, Shelburne S, Vence L M, Okhuysen P C, Jensen V B, Swennes A G, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman J L, Haydu L E, Burton E M, Gardner J M, Sirmans E, Hu J, Lazar A J, Tsujikawa T, Diab A, Tawbi H, Glitza I C, Hwu W J, Patel S P, Woodman S E, Amaria R N, Davies M A, Gershenwald J E, Hwu P, Lee J E, Zhang J, Coussens L M, Cooper Z A, Futreal P A, Daniel C R, Ajami N J, Petrosino J F, Tetzlaff M T, Sharma P, Allison J P, Jenq R R, Wargo J A. Science (New York, N.Y.) 2018;359(6371):97–103. doi: 10.1126/science.aan4236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Matson Vyara, Fessler Jessica, Bao Riyue, Chongsuwat Tara, Zha Yuanyuan, Alegre Maria-Luisa, Luke Jason J., Gajewski Thomas F. Science. 2018;359(6371):104-108. doi: 10.1126/science.aao3290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Sivan A., Corrales L., Hubert N., Williams J. B., Aquino-Michaels K., Earley Z. M., Benyamin F. W., Man Lei Y., Jabri B., Alegre M.-L., Chang E. B., Gajewski T. F. Science. 2015;350(6264):1084-1089. doi: 10.1126/science.aac4255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Routy Bertrand, Le Chatelier Emmanuelle, Derosa Lisa, Duong Connie P. M., Alou Maryam Tidjani, Daillère Romain, Fluckiger Aurélie, Messaoudene Meriem, Rauber Conrad, Roberti Maria P., Fidelle Marine, Flament Caroline, Poirier-Colame Vichnou, Opolon Paule, Klein Christophe, Iribarren Kristina, Mondragón Laura, Jacquelot Nicolas, Qu Bo, Ferrere Gladys, Clémenson Céline, Mezquita Laura, Masip Jordi Remon, Naltet Charles, Brosseau Solenn, Kaderbhai Coureche, Richard Corentin, Rizvi Hira, Levenez Florence, Galleron Nathalie, Quinquis Benoit, Pons Nicolas, Ryffel Bernhard, Minard-Colin Véronique, Gonin Patrick, Soria Jean-Charles, Deutsch Eric, Loriot Yohann, Ghiringhelli François, Zalcman Gérard, Goldwasser François, Escudier Bernard, Hellmann Matthew D., Eggermont Alexander, Raoult Didier, Albiges Laurence, Kroemer Guido, Zitvogel Laurence. Science. 2017;359(6371):91-97. doi: 10.1126/science.aan3706. [DOI] [PubMed] [Google Scholar]
  • 32.The microbiome and the hallmarks of cancer. Fulbright Laura E., Ellermann Melissa, Arthur Janelle C. PLOS Pathogens. 2017;13(9):e1006480. doi: 10.1371/journal.ppat.1006480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. Gopalakrishnan Vancheswaran, Helmink Beth A., Spencer Christine N., Reuben Alexandre, Wargo Jennifer A. Cancer Cell. 2018;33(4):570-580. doi: 10.1016/j.ccell.2018.03.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide. Viaud S., Saccheri F., Mignot G., Yamazaki T., Daillere R., Hannani D., Enot D. P., Pfirschke C., Engblom C., Pittet M. J., Schlitzer A., Ginhoux F., Apetoh L., Chachaty E., Woerther P.-L., Eberl G., Berard M., Ecobichon C., Clermont D., Bizet C., Gaboriau-Routhiau V., Cerf-Bensussan N., Opolon P., Yessaad N., Vivier E., Ryffel B., Elson C. O., Dore J., Kroemer G., Lepage P., Boneca I. G., Ghiringhelli F., Zitvogel L. Science. 2013;342(6161):971-976. doi: 10.1126/science.1240537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Vetizou M., Pitt J. M., Daillere R., Lepage P., Waldschmitt N., Flament C., Rusakiewicz S., Routy B., Roberti M. P., Duong C. P. M., Poirier-Colame V., Roux A., Becharef S., Formenti S., Golden E., Cording S., Eberl G., Schlitzer A., Ginhoux F., Mani S., Yamazaki T., Jacquelot N., Enot D. P., Berard M., Nigou J., Opolon P., Eggermont A., Woerther P.-L., Chachaty E., Chaput N., Robert C., Mateus C., Kroemer G., Raoult D., Boneca I. G., Carbonnel F., Chamaillard M., Zitvogel L. Science. 2015;350(6264):1079-1084. doi: 10.1126/science.aad1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. Paulos Chrystal M., Wrzesinski Claudia, Kaiser Andrew, Hinrichs Christian S., Chieppa Marcello, Cassard Lydie, Palmer Douglas C., Boni Andrea, Muranski Pawel, Yu Zhiya, Gattinoni Luca, Antony Paul A., Rosenberg Steven A., Restifo Nicholas P. Journal of Clinical Investigation. 2007;117(10):3140-3140. doi: 10.1172/JCI32205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.The impact of the intestinal microbiota in therapeutic responses against cancer. Goubet Anne-Gaëlle, Daillère Romain, Routy Bertrand, Derosa Lisa, M Roberti Paula, Zitvogel Laurence. Comptes rendus biologies. 2018;341(5):284–289. doi: 10.1016/j.crvi.2018.03.004. [DOI] [PubMed] [Google Scholar]
  • 38.Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Balachandran Vinod P, Łuksza Marta, Zhao Julia N, Makarov Vladimir, Moral John Alec, Remark Romain, Herbst Brian, Askan Gokce, Bhanot Umesh, Senbabaoglu Yasin, Wells Daniel K, Cary Charles Ian Ormsby, Grbovic-Huezo Olivera, Attiyeh Marc, Medina Benjamin, Zhang Jennifer, Loo Jennifer, Saglimbeni Joseph, Abu-Akeel Mohsen, Zappasodi Roberta, Riaz Nadeem, Smoragiewicz Martin, Kelley Z Larkin, Basturk Olca, Gönen Mithat, Levine Arnold J, Allen Peter J, Fearon Douglas T, Merad Miriam, Gnjatic Sacha, Iacobuzio-Donahue Christine A, Wolchok Jedd D, DeMatteo Ronald P, Chan Timothy A, Greenbaum Benjamin D, Merghoub Taha, Leach Steven D. Nature. 2017;551(7681):512–516. doi: 10.1038/nature24462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.The breakthrough of the microbiota. Kroemer Guido, Zitvogel Laurence. Nature Reviews Immunology. 2018;18(2):87-88. doi: 10.1038/nri.2018.4. [DOI] [PubMed] [Google Scholar]
  • 40.Anticancer effects of the microbiome and its products. Zitvogel Laurence, Daillère Romain, Roberti María Paula, Routy Bertrand, Kroemer Guido. Nature Reviews Microbiology. 2017;15(8):465-478. doi: 10.1038/nrmicro.2017.44. [DOI] [PubMed] [Google Scholar]
  • 41.Host-Bacterial Mutualism in the Human Intestine. Backhed F. Science. 2005;307(5717):1915-1920. doi: 10.1126/science.1104816. [DOI] [PubMed] [Google Scholar]
  • 42.Nutrients Mediate Intestinal Bacteria–Mucosal Immune Crosstalk. Ma Ning, Guo Pingting, Zhang Jie, He Ting, Kim Sung Woo, Zhang Guolong, Ma Xi. Frontiers in Immunology. 2018;9 doi: 10.3389/fimmu.2018.00005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Systematic review of the effects of the intestinal microbiota on selected nutrients and non-nutrients. Shortt Colette, Hasselwander Oliver, Meynier Alexandra, Nauta Arjen, Fernández Estefanía Noriega, Putz Peter, Rowland Ian, Swann Jonathan, Türk Jessica, Vermeiren Joan, Antoine Jean-Michel. European Journal of Nutrition. 2017;57(1):25-49. doi: 10.1007/s00394-017-1546-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Association between Faecalibacterium prausnitzii and dietary fibre in colonic fermentation in healthy human subjects. Benus Robin F. J., van der Werf Tjip S., Welling Gjalt W., Judd Patricia A., Taylor Moira A., Harmsen Hermie J. M., Whelan Kevin. British Journal of Nutrition. 2010;104(5):693-700. doi: 10.1017/S0007114510001030. [DOI] [PubMed] [Google Scholar]
  • 45.Poor antibody validation is a challenge in biomedical research: a case study for detection of c-FLIP. Bucur Octavian, Pennarun Bodvael, Stancu Andreea Lucia, Nadler Monica, Muraru Maria Sinziana, Bertomeu Thierry, Khosravi-Far Roya. Apoptosis. 2013;18(10):1154-1162. doi: 10.1007/s10495-013-0880-0. [DOI] [PubMed] [Google Scholar]

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