The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression
Open accessPublished version of a preprint
Abstract
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403–16. ©2018 AACR. See related commentary by Riquelme et al., p. 386. This article is highlighted in the In This Issue feature, p. 371
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Microbes can translocate into solid tumors via various routes.
“Microbes can translocate into solid tumors via various routes.”
From Melanoma and microbiota: Current understanding and future directions (2024) · cites this paper as [117]
Proteobacteria dominated the microbiome of pancreatic cancer, similarly to the normal duodenal microbiome.
“In contrast, Proteobacteria dominated the microbiome of pancreatic cancer, similarly to the normal duodenal microbiome makeup (16, 17, 48, 49).”
From The human tumor microbiome is composed of tumor type–specific intracellular bacteria (2020) · cites this paper as [17]
Neurons can provide serine that supports mRNA translation in PDAC.
“Neurons can also provide serine that functions to support mRNA translation in PDAC263”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [263]
Murine PDAC models show specific gut and tumor microbiomes, suggesting bacterial translocation from the intestine to the peritumoral milieu.
“Pushalkar et al. detected specific gut and tumor microbiome in murine models of PDAC, suggesting potential bacterial translocation from the intestinal tract into the peritumoral milieu”
From Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes (2019) · cites this paper as Pushalkar et al., 2018
Antibiotic bacterial ablation in an orthotopic PDAC mouse model reshapes the tumor microenvironment, induces T-cell activation, improves immune surveillance, and increases immunotherapy sensitivity.
“Bacterial ablation with antibiotics in a PDAC orthotopic mouse model reshapes the tumor microenvironment, inducing T-cell activation, improving immune surveillance, and increasing sensitivity to immunotherapy.”
From Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes (2019) · cites this paper as Pushalkar et al., 2018
Evidence suggests that intratumoral bacteria exist and are functionally active, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data across about 10 cancer types.
“Emerging evidence also suggests the existence and functional activity of intratumoral bacteria, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data on them in ~10 cancer types.”
From The microbiome and human cancer (2021) · cites this paper as [23]
Mechanistic studies of live microbiota within diverse tumor types have been limited, particularly outside the aerodigestive tract, but many of their effects on the tumor microenvironment appear to suppress local antitumor immunity.
“Mechanistic studies of live microbiota within diverse tumor types have been limited, particularly outside the aerodigestive tract, but many of their effects on the TME appear to suppress local antitumor immunity (15, 23, 34, 46, 75, 101, 102).”
From The microbiome and human cancer (2021) · cites this paper as [23]
Intratumor microbes often create tolerogenic programming through PRR ligation, with lower proportions of tumor-infiltrating lymphocytes including CD8+ T cells, and occasionally more CD4+CD25+FoxP3+ Tregs, as observed in colorectal, pancreatic, breast, and lung cancers.
“Immunologically, intratumor microbes often create tolerogenic programming through PRR ligation with lower proportions of TILs, including CD8+ T cells, and occasionally more CD4+CD25+FoxP3+ Tregs, as observed in colorectal, pancreatic, breast, and lung cancers (18, 23, 34, 46, 75, 101, 102).”
From The microbiome and human cancer (2021) · cites this paper as [23]
Modulating gut microbiota changes the intratumoral microbiome composition in pancreatic cancer, likely through communication along the pancreatic duct.
“modulation of gut microbiota influences the composition of the intratumoral microbiome in pancreatic cancer, presumably via pancreatic duct communication (15, 20, 23).”
From The microbiome and human cancer (2021) · cites this paper as [23]
Paradoxically, antibiotics also boost immunotherapy efficacy by raising PD-1 expression while eradicating the pancreatic intratumoral microbiome.
“but paradoxically they improve immunotherapy efficacy by upregulating PD-1 expression when eliminating the pancreatic intratumoral microbiome (23).”
From The microbiome and human cancer (2021) · cites this paper as [23]
Research in lung, colon, and pancreatic cancer indicates that removing intratumoral microbiota can halt tumor-promoting inflammation, lower cellular proliferation, or shift a tolerogenic tumor microenvironment toward an immunogenic one.
“Several studies in lung, colon, and pancreatic cancer suggest that eliminating intratumoral microbiota can check tumor-promoting inflammatory processes, reduce cellular proliferation, or convert a tolerogenic TME to an immunogenic one (18, 19, 23, 46).”
From The microbiome and human cancer (2021) · cites this paper as [23]
CD8+ T cells can induce the regression of PDAC when activated by the intestinal microbiota.
“CD8+ T cells can induce the regression of PDAC when activated by the intestinal microbiota11,21.”
From Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer (2023) · cites this paper as [21]
A prior report suggested that the microbiome can promote tumor growth through TLR-dependent local innate inflammation with Bifidobacterium enrichment.
“A recent report suggested that the microbiome can promote tumor growth by TLR-dependent stimulation of innate inflammation locally with enrichment of Bifidobacterium (Pushalkar et al., 2018).”
From Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity (2022) · cites this paper as Pushalkar et al., 2018
Intra-tumor microbiota in pancreatic adenocarcinoma in mice and humans promotes carcinogenesis through induction of a tolerogenic immune program.
“intra-tumor microbiota in pancreatic adenocarcinoma (PDAC) in mice and humans promotes carcinogenesis through induction of a tolerogenic immune program”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [197]
PD-1 expression upregulation caused by bacterial elimination could reverse immune tolerance to benefit the PD-1 blocking therapy.
“In addition, PD-1 expression upregulation caused by bacterial elimination could reverse immune tolerance to benefit the PD-1 blocking therapy.”
From Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy (2020) · cites this paper as [59]
Bacterial composition differs between normal pancreas and pancreatic ductal adenocarcinoma.
“Pushalkar et al. (59) showed a difference in bacterial composition between normal pancreas and pancreatic ductal adenocarcinoma (PDAC).”
From Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy (2020) · cites this paper as [59]
Bacterial ablation led to a reduction in myeloid-derived suppressor cells, increased M1 macrophage differentiation, enhanced CD4+ T-cell differentiation and CD8+ T-cell activation.
“Bacterial ablation led to a reduction in myeloid-derived suppressor cells, increased M1 macrophage differentiation, enhanced CD4+ T-cell differentiation and CD8+ T-cell activation.”
From Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy (2020) · cites this paper as [59]
In a PDAC microbiome study, endogenous bacterial dysbiosis triggered immune suppression, but Treg differentiation did not differ in PDAC-bearing and WT mice.
“In their study on PDAC microbiome, Pushalkar et al. (59) found that, although endogenous bacterial dysbiosis triggered immune suppression, Treg differentiation did not differ in PDAC-bearing and WT mice.”
From Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy (2020) · cites this paper as [59]
Blautia obeum, Roseburia intestinalis, and some combination of antibiotics compromised the efficacy of immunotherapy.
“However, Blautia obeum, Roseburia intestinalis, and some combination of antibiotics (56, 59, 77) compromised the efficacy of immunotherapy (Table 1).”
From Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy (2020) · cites this paper as [59]
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Cites
QIIME allows analysis of high-throughput community sequencing data
Caporaso, J. G., Kuczynski, J., Stombaugh, J., Bittinger, K., Bushman, F. D., Costello, E. K., Fierer, N., Peña, A. G., Goodrich, J. K., Gordon, J. I., et al. (2010) · Nature Methods · doi:10.1038/nmeth.f.303 · Cited by 34,887 · see citing works
Search and clustering orders of magnitude faster than BLAST
Edgar, R. C. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq461 · Cited by 20,617 · see citing works
Metagenomic biomarker discovery and explanation
Segata, N., Izard, J., Waldron, L., Gevers, D., Miropolsky, L., Garrett, W. S., & Huttenhower, C. (2011) · Genome Biology · doi:10.1186/gb-2011-12-6-r60 · Cited by 16,192 · see citing works
Siegel, R. L., Miller, K. D., & Jemal, A. (2016) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21332 · Cited by 16,003 · see citing works
Klindworth, A., Pruesse, E., Schweer, T., Peplies, J., Quast, C., Horn, M., & Glöckner, F. O. (2013) · Nucleic Acids Research · doi:10.1093/nar/gks808 · Cited by 8,850 · see citing works
Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms
Caporaso, J. G., Lauber, C. L., Walters, W. A., Berg-Lyons, D., Huntley, J., Fierer, N., Owens, S. M., Betley, J., Fraser, L., Bauer, M., et al. (2012) · The ISME Journal · doi:10.1038/ismej.2012.8 · Cited by 8,839 · see citing works
FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix
Price, M. N., Dehal, P. S., & Arkin, A. P. (2009) · Molecular Biology and Evolution · doi:10.1093/molbev/msp077 · Cited by 5,602 · see citing works
Commensal <i>Bifidobacterium</i> 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., et al. (2015) · Science · doi:10.1126/science.aac4255 · Cited by 3,888 · see citing works
Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR ampliconsPreprint
Haas, B. J., Gevers, D., Earl, A. M., Feldgarden, M., Ward, D. V., Giannoukos, G., Ciulla, D., Tabbaa, D., Highlander, S. K., Sodergren, E. J., et al. (2011) · Genome Research · doi:10.1101/gr.112730.110 · Cited by 3,451 · see citing works
Transitions in bacterial communities along the 2000 km salinity gradient of the Baltic Sea
Herlemann, D. P. R., Labrenz, M., Jürgens, K., Bertilsson, S., Waniek, J. J., & Andersson, A. F. (2011) · The ISME Journal · doi:10.1038/ismej.2011.41 · Cited by 2,885 · see citing works
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609 · see citing works
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471 · see citing works
Large-scale gene function analysis with the PANTHER classification system
Mi, H., Muruganujan, A., Casagrande, J. T., & Thomas, P. D. (2013) · Nature Protocols · doi:10.1038/nprot.2013.092 · Cited by 2,422 · see citing works
PANDAseq: paired-end assembler for Illumina sequences
Masella, A. P., Bartram, A. K., Truszkowski, J. M., Brown, D. G., & Neufeld, J. D. (2012) · BMC Bioinformatics · doi:10.1186/1471-2105-13-31 · Cited by 2,132 · see citing works
Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., Gavert, N., Zwang, Y., Cooper, Z. A., Shee, K., et al. (2017) · Science · doi:10.1126/science.aah5043 · Cited by 1,817 · see citing works
Schwabe, R. F., & Jobin, C. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3610 · Cited by 1,689 · see citing works
Garrett, W. S. (2015) · Science · doi:10.1126/science.aaa4972 · Cited by 1,404 · see citing works
Hruban, R. H., Adsay, N. V., Albores–Saavedra, J., Compton, C., Garrett, E. S., Goodman, S. N., Kern, S. E., Klimstra, D. S., Klöppel, G., Longnecker, D. S., et al. (2001) · The American Journal of Surgical Pathology · doi:10.1097/00000478-200105000-00003 · Cited by 1,126 · see citing works
Dynamics of the immune reaction to pancreatic cancer from inception to invasion
Clark, C. E., Hingorani, S. R., Mick, R., Combs, C., Tuveson, D. A., & Vonderheide, R. H. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0175 · Cited by 990 · see citing works
Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer
Ino, Y., Yamazaki–Itoh, R., Shimada, K., Iwasaki, M., Kosuge, T., Kanai, Y., & Hiraoka, N. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.32 · Cited by 853 · see citing works
Hiraoka, N., Onozato, K., Kosuge, T., & Hirohashi, S. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0369 · Cited by 831 · see citing works
Plottel, C. S., & Blaser, M. J. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.10.003 · Cited by 743 · see citing works
Goodrich, J. K., Di Rienzi, S. C., Poole, A. C., Koren, O., Walters, W. A., Caporaso, J. G., Knight, R., & Ley, R. E. (2014) · Cell · doi:10.1016/j.cell.2014.06.037 · Cited by 714 · see citing works
Monte, L. B. D., Reni, M., Tassi, E., Clavenna, D., Papa, I., Recalde, H. R., Braga, M., Carlo, V. D., Doglioni, C., & Protti, M. P. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20101876 · Cited by 692 · see citing works
The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression
Seifert, L., Werba, G., Tiwari, S., Ly, N. N. G., Alothman, S., Alqunaibit, D., Avanzi, A., Barilla, R., Daley, D., Greco, S. H., et al. (2016) · Nature · doi:10.1038/nature17403 · Cited by 606 · see citing works
Self-citationAdvancing Our Understanding of the Human Microbiome Using QIIME
Navas-Molina, J. A., Peralta‐Sánchez, J. M., González, A., McMurdie, P. J., Vázquez‐Baeza, Y., Xu, Z. Z., Ursell, L. K., Lauber, C. L., Zhou, H., Song, S. J., et al. (2013) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-407863-5.00019-8 · Cited by 603 · see citing works
Intestinal microbiota in health and disease: Role of bifidobacteria in gut homeostasis
Tojo, R. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i41.15163 · Cited by 533 · see citing works
Fukunaga, A., Miyamoto, M., Cho, Y., Murakami, S., Kawarada, Y., Oshikiri, T., Kato, K., Kurokawa, T., Suzuoki, M., Nakakubo, Y., et al. (2003) · Pancreas · doi:10.1097/00006676-200401000-00023 · Cited by 532 · see citing works
Depletion of Murine Intestinal Microbiota: Effects on Gut Mucosa and Epithelial Gene Expression
Reikvam, D. H., Erofeev, A. S., Sandvik, A., Grcic, V., Jahnsen, F. L., Gaustad, P., McCoy, K. D., Macpherson, A. J., Meza‐Zepeda, L. A., & Johansen, F. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017996 · Cited by 531 · see citing works
Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice
Bedoret, D., Wallemacq, H., Marichal, T., Desmet, C., Quesada Calvo, F., Henry, E., Closset, R., Dewals, B., Thielen, C., Gustin, P., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39717 · Cited by 399 · see citing works
Complex Species Interactions and the Dynamics of Ecological Systems: Long-Term Experiments
Brown, J. H., Whitham, T. G., Ernest, S. K. M., & Gehring, C. A. (2001) · Science · doi:10.1126/science.293.5530.643 · Cited by 393 · see citing works
Daley, D., Mani, V. R. K., Mohan, N., Akkad, N., Ochi, A., Heindel, D. W., Lee, K. B., Zambirinis, C. P., Pandian, G. S. D. B., Savadkar, S., et al. (2017) · Nature Medicine · doi:10.1038/nm.4314 · Cited by 383 · see citing works
Self-citationPushalkar, S., Ji, X., Li, Y., Estilo, C. L., Ramanathan, Y., Singh, B., Li, X., & Saxena, D. B. (2012) · BMC Microbiology · doi:10.1186/1471-2180-12-144 · Cited by 344 · see citing works
Self-citationRole of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma
Zheng, L., Xue, J., Jaffee, E. M., & Habtezion, A. (2013) · Gastroenterology · doi:10.1053/j.gastro.2012.12.042 · Cited by 323 · see citing works
Rutkowski, M. R., Stephen, T. L., Svoronos, N., Allegrezza, M. J., Tesone, A. J., Perales-Puchalt, A., Brencicova, E., Escovar-Fadul, X., Nguyen, J. M., Cadungog, M. G., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.11.009 · Cited by 311 · see citing works
Ochi, A., Nguyen, A. H., Bedrosian, A. S., Mushlin, H. M., Zarbakhsh, S., Barilla, R., Zambirinis, C. P., Fallon, N. C., Rehman, A. U., Pylayeva‐Gupta, Y., et al. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20111706 · Cited by 306 · see citing works
Self-citationThe microbiome quality control project: baseline study design and future directions
Sinha, R. R., Abnet, C. C., White, O. R., Knight, R. D., & Huttenhower, C. (2015) · Genome biology · doi:10.1186/s13059-015-0841-8 · Cited by 267 · see citing works
NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma
Daley, D., Mani, V. R., Mohan, N., Akkad, N., Pandian, G. S. D. B., Savadkar, S., Lee, K. B., Torres-Hernandez, A., Aykut, B., Diskin, B., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161707 · Cited by 244 · see citing works
Self-citationEmerging roles of the microbiome in cancer
Bultman, S. J. (2014) · Carcinogenesis · doi:10.1093/carcin/bgt392 · Cited by 239 · see citing works
Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans
Sanapareddy, N., Legge, R. M., Jovov, B., McCoy, A. N., Burcal, L., Araújo-Pérez, F., Randall, T. A., Galanko, J. A., Benson, A. K., Sandler, R. S., et al. (2012) · The ISME Journal · doi:10.1038/ismej.2012.43 · Cited by 217 · see citing works
Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice
Seifert, L., Werba, G., Tiwari, S., Ly, N. N. G., Nguy, S., Alothman, S., Alqunaibit, D., Avanzi, A., Daley, D., Barilla, R., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.070 · Cited by 193 · see citing works
Self-citationSunde, P. T., Olsen, I., Göbel, U. B., Theegarten, D., Winter, S., Debelian, G., Tronstad, L., & Moter, A. (2003) · Microbiology · doi:10.1099/mic.0.26077-0 · Cited by 193 · see citing works
Ibrahim, J., Nguyen, A. H., Rehman, A. U., Ochi, A., Jamal, M., Graffeo, C. S., Henning, J. R., Zambirinis, C. P., Fallon, N. C., Barilla, R., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.06.003 · Cited by 176 · see citing works
Self-citationLarge-scale contamination of microbial isolate genomes by Illumina PhiX control
Mukherjee, S., Huntemann, M., Ivanova, N., Kyrpides, N. C., & Pati, A. (2015) · Standards in Genomic Sciences · doi:10.1186/1944-3277-10-18 · Cited by 167 · see citing works
TLR9 ligation in pancreatic stellate cells promotes tumorigenesis
Zambirinis, C. P., Levie, E., Nguy, S., Avanzi, A., Barilla, R., Xu, Y., Seifert, L., Daley, D., Greco, S. H., Deutsch, M., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20142162 · Cited by 164 · see citing works
Self-citationOtt, S. J., Musfeldt, M., Ullmann, U., Hampe, J., & Schreiber, S. (2004) · Journal of Clinical Microbiology · doi:10.1128/jcm.42.6.2566-2572.2004 · Cited by 148 · see citing works
The Gut Microbiome in Health and Disease
Owyang, C., & Wu, G. D. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.03.032 · Cited by 117 · see citing works
Role of Fatty-Acid Synthesis in Dendritic Cell Generation and Function
Rehman, A. U., Hemmert, K. C., Ochi, A., Jamal, M., Henning, J. R., Barilla, R., Quesada, J. P., Zambirinis, C. P., Tang, K., Ego-Osuala, M., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202312 · Cited by 101 · see citing works
Self-citationDefensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection
Pîrcălăbioru, G. G., Aviello, G., Kubica, M., Zhdanov, A. V., Paclet, M., Brennan, L., Hertzberger, R. Y., Papkovsky, D. B., Bourke, B., & Knaus, U. G. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.04.007 · Cited by 98 · see citing works
Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw
Pushalkar, S., Li, X., Kurago, Z., Ramanathapuram, L. V., Matsumura, S., Fleisher, K. E., Glickman, R. S., Yan, W., Li, Y., & Saxena, D. B. (2014) · International Journal of Oral Science · doi:10.1038/ijos.2014.46 · Cited by 77 · see citing works
Self-citationAltered Tissue Metabolites Correlate with Microbial Dysbiosis in Colorectal Adenomas
Nugent, J. L., McCoy, A. N., Addamo, C. J., Jia, W. P., Sandler, R. S., & Keku, T. O. (2014) · Journal of Proteome Research · doi:10.1021/pr4009783 · Cited by 58 · see citing works
Protocol for Rapid Fluorescence In Situ Hybridization of Bacteria in Cryosections of Microarthropods
Thimm, T., & Tebbe, C. C. (2003) · Applied and Environmental Microbiology · doi:10.1128/aem.69.5.2875-2878.2003 · Cited by 32 · see citing works
Induction of TRIF- or MYD88-dependent pathways perturbs cell cycle regulation in pancreatic cancer
Ochi, A., Barilla, R., Greco, S. H., Deutsch, M., & Miller, G. (2013) · Cell Cycle · doi:10.4161/cc.24488 · Cited by 20 · see citing works
Self-citationChoi, Y. S., Kim, Y. C., Baek, K. J., et al. (2015) · Journal of Visualized Experiments · doi:10.3791/52836 · Cited by 16 · see citing works
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Hanahan, D. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1059 · Cited by 9,887 · see citing works
Interaction between microbiota and immunity in health and disease
Zheng, D., Liwinski, T., & Elinav, E. (2020) · Cell Research · doi:10.1038/s41422-020-0332-7 · Cited by 3,947 · see citing works
The human tumor microbiome is composed of tumor type–specific intracellular bacteria
Nejman, D., Livyatan, I., Fuks, G., Gavert, N., Zwang, Y., Geller, L. T., Rotter-Maskowitz, A., Weiser, R., Mallel, G., Gigi, E., et al. (2020) · Science · doi:10.1126/science.aay9189 · Cited by 2,464 · see citing works
Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes
Riquelme, E., Zhang, Y., Zhang, L., Montiel, M., Zoltan, M., Dong, W., Quesada, P., Sahin, I., Chandra, V., San Lucas, A., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.008 · Cited by 1,577 · see citing works
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Sepich-Poore, G. D., Zitvogel, L., Straussman, R., Hasty, J., Wargo, J. A., & Knight, R. (2021) · Science · doi:10.1126/science.abc4552 · Cited by 1,332 · see citing works
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
The microbiome, cancer, and cancer therapy
Helmink, B. A., Khan, M. A. W., Hermann, A., Gopalakrishnan, V., & Wargo, J. A. (2019) · Nature Medicine · doi:10.1038/s41591-019-0377-7 · Cited by 1,200 · see citing works
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Fu, A., Yao, B., Dong, T., Chen, Y., Yao, J., Liu, Y., Li, H., Bai, H., Liu, X., Zhang, Y., et al. (2022) · Cell · doi:10.1016/j.cell.2022.02.027 · Cited by 981 · see citing works
Self-citationThe fungal mycobiome promotes pancreatic oncogenesis via activation of MBL
Aykut, B., Pushalkar, S., Chen, R., Li, Q., Abengozar, R., Kim, J. I., Shadaloey, S. A., Wu, D., Preiss, P., Verma, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1608-2 · Cited by 883 · see citing works
Self-citationHezaveh, K., Shinde, R. S., Klötgen, A., Halaby, M. J., Lamorte, S., Ciudad, M. T., Quevedo, R., Neufeld, L., Liu, Z. Q., Jin, R., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.01.006 · Cited by 746 · see citing works
The hallmarks of successful anticancer immunotherapy
Galluzzi, L., Chan, T. A., Kroemer, G., Wolchok, J. D., & López-Soto, A. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat7807 · Cited by 575 · see citing works
Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions
Narunsky-Haziza, L., Sepich-Poore, G. D., Livyatan, I., Asraf, O., Martino, C., Nejman, D., Gavert, N., Stajich, J. E., Amit, G., González, A., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.005 · Cited by 538 · see citing works
Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer
Tintelnot, J., Xu, Y., Lesker, T. R., Schönlein, M., Konczalla, L., Giannou, A. D., Pelczar, P., Kylies, D., Puelles, V. G., Bielecka, A. A., et al. (2023) · Nature · doi:10.1038/s41586-023-05728-y · Cited by 478 · see citing works
Identification of bacteria-derived HLA-bound peptides in melanoma
Kalaora, S., Nagler, A., Nejman, D., Alon, M., Barbolin, C., Barnea, E., Ketelaars, S. L. C., Cheng, K., Vervier, K., Shental, N., et al. (2021) · Nature · doi:10.1038/s41586-021-03368-8 · Cited by 457 · see citing works
The role of gut microbiota in cancer treatment: friend or foe?
Cheng, W. Y., Wu, C.-Y., & Yu, J. (2020) · Gut · doi:10.1136/gutjnl-2020-321153 · Cited by 384 · see citing works
Matson, V., Chervin, C. S., & Gajewski, T. F. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.11.041 · Cited by 385 · see citing works
Modulating the microbiome to improve therapeutic response in cancer
McQuade, J. L., Daniel, C. R., Helmink, B. A., & Wargo, J. A. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30952-5 · Cited by 376 · see citing works
Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer
Li, C., Xu, X., Wei, S., Jiang, P., Xue, L., & Wang, J. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001341 · Cited by 360 · see citing works
Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data
Connor, A. A., & Gallinger, S. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00418-1 · Cited by 369 · see citing works
Mirji, G., Worth, A., Bhat, S. A., El Sayed, M., Kannan, T., Goldman, A. R., Tang, H.-Y., Liu, Q., Auslander, N., Dang, C. V., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abn0704 · Cited by 327 · see citing works
Gut microbiome, big data and machine learning to promote precision medicine for cancer
Cammarota, G., Ianiro, G., Ahern, A., Carbone, C., Temko, A., Claesson, M. J., Gasbarrini, A., & Tortora, G. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0327-3 · Cited by 324 · see citing works
A faecal microbiota signature with high specificity for pancreatic cancer
Kartal, E., Schmidt, T. S. B., Molina-Montes, E., Rodríguez-Perales, S., Wirbel, J., Maistrenko, O. M., Akanni, W. A., Alashkar Alhamwe, B., Alves, R. J., Carrato, A., et al. (2022) · Gut · doi:10.1136/gutjnl-2021-324755 · Cited by 290 · see citing works
Chen, Y., Yang, S., Tavormina, J., Tampe, D., Zeisberg, M., Wang, H., Mahadevan, K. K., Wu, C.-J., Sugimoto, H., Chang, C.-C., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.06.011 · Cited by 289 · see citing works
Le Noci, V., Guglielmetti, S., Arioli, S., Camisaschi, C., Bianchi, F., Sommariva, M., Storti, C., Triulzi, T., Castelli, C., Balsari, A., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.08.090 · Cited by 270 · see citing works
Nagata, N., Nishijima, S., Kojima, Y., Hisada, Y., Imbe, K., Miyoshi-Akiyama, T., Suda, W., Kimura, M., Aoki, R., Sekine, K., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.03.054 · Cited by 209 · see citing works
Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer
Gaiser, R. A., Halimi, A., Alkharaan, H., Lu, L., Davanian, H., Healy, K., Hugerth, L. W., Ateeb, Z., Valente, R., Fernández Moro, C., et al. (2019) · Gut · doi:10.1136/gutjnl-2018-317458 · Cited by 227 · see citing works
High fat diet, gut microbiome and gastrointestinal cancer
Tong, Y., Gao, H., Qi, Q., Liu, X., Li, J., Gao, J., Li, P., Wang, Y., Du, L., & Wang, C. (2021) · Theranostics · doi:10.7150/thno.56157 · Cited by 205 · see citing works
Tumor microbiome links cellular programs and immunity in pancreatic cancer
Ghaddar, B., Biswas, A., Harris, C., Omary, M. B., Carpizo, D. R., Blaser, M. J., & De, S. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.09.009 · Cited by 181 · see citing works
Microbiota-Centered Interventions: The Next Breakthrough in Immuno-Oncology?
Derosa, L., Routy, B., Desilets, A., Daillère, R., Terrisse, S., Kroemer, G., & Zitvogel, L. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0236 · Cited by 170 · see citing works
Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy
Shui, L., Yang, X., Li, J., Yi, C., Sun, Q., & Zhu, H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02989 · Cited by 115 · see citing works
The Impact of Intratumoral and Gastrointestinal Microbiota on Systemic Cancer Therapy
Cogdill, A. P., Gaudreau, P. O., Arora, R., Gopalakrishnan, V., & Wargo, J. A. (2018) · Trends in Immunology · doi:10.1016/j.it.2018.09.007 · Cited by 98 · see citing works
Melanoma and microbiota: Current understanding and future directions
Routy, B., Jackson, T., Mählmann, L., Baumgartner, C. K., Blaser, M., Byrd, A., Corvaia, N., Couts, K., Davar, D., Derosa, L., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2023.12.003 · Cited by 89 · see citing works
Perusina Lanfranca, M., Zhang, Y., Girgis, A., Kasselman, S., Lazarus, J., Kryczek, I., Delrosario, L., Rhim, A., Koneva, L., Sartor, M., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.12.010 · Cited by 81 · see citing works
Can we harness the microbiota to enhance the efficacy of cancer immunotherapy?
Finlay, B. B., Goldszmid, R., Honda, K., Trinchieri, G., Wargo, J., & Zitvogel, L. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0374-6 · Cited by 81 · see citing works
Goubet, A.-G., Lordello, L., Alves Costa Silva, C., Peguillet, I., Gazzano, M., Mbogning-Fonkou, M. D., Thelemaque, C., Lebacle, C., Thibault, C., Audenet, F., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0201 · Cited by 86 · see citing works
Zhang, Z., Tanaka, I., Pan, Z., Ernst, P. B., Kiyono, H., & Kurashima, Y. (2022) · European Journal of Immunology · doi:10.1002/eji.202149532 · Cited by 69 · see citing works
Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis
Ammer-Herrmenau, C., Antweiler, K. L., Asendorf, T., Beyer, G., Buchholz, S. M., Cameron, S., Capurso, G., Damm, M., Dang, L., Frost, F., et al. (2024) · Gut · doi:10.1136/gutjnl-2023-330987 · Cited by 67 · see citing works
McQuade, J. L., Ologun, G. O., Arora, R., & Wargo, J. A. (2020) · Current Oncology Reports · doi:10.1007/s11912-020-00913-y · Cited by 63 · see citing works
Role of the tumor microenvironment in cancer hallmarks and targeted therapy (Review)
Naser, R., Fakhoury, I., El‑Fouani, A., Abi‑Habib, R., & El‑Sibai, M. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5471 · Cited by 61 · see citing works
Circumventing senescence is associated with stem cell properties and metformin sensitivity
Deschênes‐Simard, X., Parisotto, M., Rowell, M., Le Calvé, B., Igelmann, S., Moineau‐Vallée, K., Saint‐Germain, E., Kalegari, P., Bourdeau, V., Kottakis, F., et al. (2019) · Aging Cell · doi:10.1111/acel.12889 · Cited by 45 · see citing works
Gao, Z., Jiang, A., Li, Z., Zhu, L., Mou, W., Shen, W., Luo, P., Tang, B., Zhang, J., & Lin, A. (2025) · Med Research · doi:10.1002/mdr2.70006 · Cited by 51 · see citing works
The metabolic dialogue between intratumoural microbes and cancer: implications for immunotherapy
Situ, Y., Zhang, P., Zhang, C., Jiang, A., Zhang, N., Zhu, L., Mou, W., Liu, Z., Wong, H. Z. H., Zhang, J., et al. (2025) · eBioMedicine · doi:10.1016/j.ebiom.2025.105708 · Cited by 45 · see citing works
Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance
Manzoor, S., Muhammad, J. S., Maghazachi, A. A., & Hamid, Q. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.924290 · Cited by 45 · see citing works
Facts and Hopes for Gut Microbiota Interventions in Cancer Immunotherapy
Davar, D., & Zarour, H. M. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-1129 · Cited by 40 · see citing works
Computational methods and challenges in analyzing intratumoral microbiome data
Wang, Q., Liu, Z., Ma, A., Li, Z., Liu, B., & Ma, Q. (2023) · Trends in Microbiology · doi:10.1016/j.tim.2023.01.011 · Cited by 37 · see citing works
Sepich‐Poore, G. D., Guccione, C., Laplane, L., Pradeu, T., Curtius, K., & Knight, R. (2022) · BioEssays · doi:10.1002/bies.202100252 · Cited by 33 · see citing works
Bugs as drugs: The role of microbiome in cancer focusing on immunotherapeutics
Araujo, D. V., Watson, G. A., Oliva, M., Heirali, A., Coburn, B., Spreafico, A., & Siu, L. L. (2021) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102125 · Cited by 29 · see citing works
- Authors
- Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., Mohan, N., Aykut, B., Usyk, M., Torres, L. E., Werba, G., Zhang, K., Guo, Y., Li, Q., Akkad, N., Lall, S., Wadowski, B., Gutierrez, J., Kochen Rossi, J. A., Herzog, J. W., Diskin, B., Torres-Hernandez, A., Leinwand, J., Wang, W., Taunk, P. S., Savadkar, S., Janal, M., Saxena, A., Li, X., Cohen, D., Sartor, R. B., Saxena, D., & Miller, G.
- Affiliations
- New York University (US)
- 2S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
- NYU Langone Health (US)
- University of North Carolina at Chapel Hill (US)
- The Graduate Center, CUNY (US)
- Corresponding author
- Saxena, Deepak
- Miller, George
- ORCID
- Pushalkar, Smruti
- Daley, Donnele
- Zambirinis, Constantinos P.
- Kurz, Emma
- Mishra, Ankita
- Aykut, Berk
- Usyk, Mykhaylo
- Werba, Gregor
- Zhang, Kevin
- Guo, Yuqi
- Li, Qianhao
- Wadowski, Benjamin
- Gutierrez, Johana
- Herzog, Jeremy W.
- Diskin, Brian
- Torres-Hernandez, Alejandro
- Wang, Wei
- Janal, Malvin
- Saxena, Anjana
- Li, Xin
- Cohen, Deirdre
- Sartor, R. Balfour
- Saxena, Deepak
- Miller, George
- Venue
- Cancer Discovery
- Published
- 2018-04-01
- Volume
- 8
- Issue
- 4
- Pages
- 403-416
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6225783
- OpenAlex
- W2790589159
- Cited by
- 1,400
- References
- 54
- Citations by year
- 2026: 161 · 2025: 215 · 2024: 199 · 2023: 216 · 2022: 201 · 2021: 167 · 2020: 142 · 2019: 72 · 2018: 25
- FWCI
- 38.07
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-12-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P40OD010995, UL1TR001445)
- National Cancer Institute (R01CA206105, R21CA175794, R01CA180277, R01CA168611, R21CA155649, P30CA016087)
- National Institute of General Medical Sciences (T32GM007308)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034987)
- National Institute of Dental and Craniofacial Research (R01DE025992)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- pancreatic ductal adenocarcinoma, tumor immunosuppression, myeloid-derived suppressor cells, CD8+ T cell activation, Th1 differentiation, PD-1 expression, immune checkpoint inhibitors, Toll-like receptor signaling, monocytic cells, bacterial transfer, tumor microenvironment, T cell anergy
- MeSH terms
- Animals, Bacteria, Cell Differentiation, Female, Humans, Male, Monocytes, Pancreatic Neoplasms, Signal Transduction, Toll-Like Receptors, Mice, Carcinogenesis, Microbiota
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