Curated Papers > High-impact authoritative literature on "tumor microenvironment"

Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment.

Literature Information

DOI	10.1126/science.1240527
PMID	24264989
Journal	Science (New York, N.Y.)
Impact Factor	45.8
JCR Quartile	Q1
Publication Year	2013
Times Cited	1157
Keywords	commensal bacteria, tumor microenvironment, immunotherapy, chemotherapy, inflammation
Literature Type	Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
ISSN	0036-8075
Pages	967-70
Issue	342(6161)
Authors	Noriho Iida, Amiran Dzutsev, C Andrew Stewart, Loretta Smith, Nicolas Bouladoux, Rebecca A Weingarten, Daniel A Molina, Rosalba Salcedo, Timothy Back, Sarah Cramer, Ren-Ming Dai, Hiu Kiu, Marco Cardone, Shruti Naik, Anil K Patri, Ena Wang, Francesco M Marincola, Karen M Frank, Yasmine Belkaid, Giorgio Trinchieri, Romina S Goldszmid

TL;DR

This study investigates the role of gut microbiota in modulating inflammation within the tumor microenvironment and its impact on cancer therapy effectiveness. The findings reveal that disruption of microbiota impairs the response of tumors to immunotherapy and chemotherapy, highlighting the necessity of an intact microbiota for optimal treatment outcomes by influencing myeloid-derived cell functions.

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commensal bacteria · tumor microenvironment · immunotherapy · chemotherapy · inflammation

Abstract

The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.

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Primary Questions Addressed

1. How do specific types of commensal bacteria influence the immune response in the tumor microenvironment?
2. What are the mechanisms by which the gut microbiota modulates myeloid-derived cell functions during cancer therapy?
3. Can the restoration of the microbiota enhance the efficacy of existing cancer treatments, and if so, how?
4. What role does inflammation play in the interaction between commensal bacteria and cancer therapies?
5. How might personalized microbiome interventions be integrated into cancer treatment protocols to improve patient outcomes?

Key Findings

Research Background and Objective

The study investigates the role of the gut microbiota in modulating the tumor microenvironment and influencing the efficacy of cancer therapies, particularly focusing on the inflammatory response. It aims to understand how commensal bacteria affect cancer treatment outcomes, especially in the context of immunotherapy and chemotherapy.

Main Methods/Materials/Experimental Design

The research utilized a mouse model to explore the effects of the gut microbiota on tumor response to therapies. Key methodologies included:

1. Antibiotic Treatment: Mice were treated with an antibiotic cocktail (vancomycin, imipenem, and neomycin) starting three weeks before tumor inoculation to disrupt the microbiota.
2. Tumor Models: Three transplantable tumors (EL4 lymphoma, MC38 colon carcinoma, B16 melanoma) were used, injected subcutaneously into the mice.
3. Therapeutic Interventions: Mice received treatments with CpG-oligodeoxynucleotides (ODN) combined with anti-IL-10 receptor antibodies, and platinum-based chemotherapies (oxaliplatin and cisplatin).
4. Gene Expression Analysis: Tumors were analyzed for gene expression related to inflammation, immune responses, and cytokine production using real-time PCR and Nanostring nCounter technology.
5. Microbiota Composition Analysis: Fecal samples were analyzed for microbial diversity and composition to correlate with TNF production in tumors.

Key Results and Findings

• Impact of Antibiotics: Antibiotic treatment impaired tumor response to both immunotherapy and chemotherapy, leading to reduced cytokine production and tumor necrosis.
• Inflammatory Response: Mice with disrupted microbiota exhibited down-regulation of inflammatory genes and diminished TNF production in response to therapy.
• Restoration of Response: Administration of bacterial lipopolysaccharide (LPS) restored TNF production in antibiotic-treated mice, indicating the role of commensal bacteria in priming myeloid cells for inflammatory responses.
• Chemotherapy Efficacy: The efficacy of oxaliplatin and cisplatin was significantly reduced in antibiotic-treated and germ-free mice, suggesting that microbiota influences the cytotoxic effects of these drugs through modulation of reactive oxygen species (ROS) production.

Main Conclusions/Significance/Innovation

The study concludes that an intact gut microbiota is crucial for optimal anti-tumor responses to both immunotherapy and chemotherapy. The findings highlight the potential for microbiota manipulation as a strategy to enhance cancer treatment efficacy. The research underscores the intricate relationship between the microbiome and the immune response in the tumor microenvironment, paving the way for novel therapeutic approaches that incorporate microbiota modulation.

Research Limitations and Future Directions

• Limitations: The study primarily used mouse models, which may not fully replicate human responses. The specific bacterial species responsible for the observed effects were not completely identified.
• Future Directions: Further research is needed to delineate the specific mechanisms by which different bacterial species influence tumor responses. Clinical studies are also warranted to explore the implications of microbiota manipulation in cancer therapies for humans.

Aspect	Findings
Antibiotic Impact	Impaired tumor response, reduced cytokine production, and tumor necrosis.
Inflammatory Gene Regulation	Down-regulation of inflammatory genes in antibiotic-treated mice.
Chemotherapy Efficacy	Reduced effectiveness of oxaliplatin and cisplatin in mice lacking gut microbiota.
Restoration Mechanism	LPS administration restored TNF production and tumor response in antibiotic-treated mice.
Clinical Implications	Potential for microbiota modulation to enhance cancer treatment outcomes.

References

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Literatures Citing This Work

1. Tumour immunology: Anticancer drugs need bugs. - Yvonne Bordon - Nature reviews. Immunology (2014)
2. Chemotherapy, immunity and microbiota--a new triumvirate? - Michael Karin;Christian Jobin;Frances Balkwill - Nature medicine (2014)
3. Tumour microenvironment: bacterial balance affects cancer treatment. - Isabel Lokody - Nature reviews. Cancer (2014)
4. Host immune response to infection and cancer: unexpected commonalities. - Romina S Goldszmid;Amiran Dzutsev;Giorgio Trinchieri - Cell host & microbe (2014)
5. Microbes, microbiota, and colon cancer. - Cynthia L Sears;Wendy S Garrett - Cell host & microbe (2014)
6. The intestinal metabolome: an intersection between microbiota and host. - Luke K Ursell;Henry J Haiser;Will Van Treuren;Neha Garg;Lavanya Reddivari;Jairam Vanamala;Pieter C Dorrestein;Peter J Turnbaugh;Rob Knight - Gastroenterology (2014)
7. Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics. - Henry J Haiser;Kristen L Seim;Emily P Balskus;Peter J Turnbaugh - Gut microbes (2014)
8. Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine. - Johan Vande Voorde;Suna Sabuncuoğlu;Sam Noppen;Anders Hofer;Farahnaz Ranjbarian;Steffen Fieuws;Jan Balzarini;Sandra Liekens - The Journal of biological chemistry (2014)
9. Role of the microbiota in immunity and inflammation. - Yasmine Belkaid;Timothy W Hand - Cell (2014)
10. Individualized medicine from prewomb to tomb. - Eric J Topol - Cell (2014)

... (1147 more literatures)

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