Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation—A Special Reference to Colorectal Cancer

Over the last few years, immunotherapy has been considered as a key player in the treatment of solid tumors. Immune checkpoint inhibitors (ICIs) have become the breakthrough treatment, with prolonged responses and improved survival results. ICIs use the immune system to defeat cancer by breaking the axes that allow tumors to escape immune surveillance. Innate and adaptive immunity are involved in mechanisms against tumor growth. The gut microbiome and its role in such mechanisms is a relatively new study field. The presence of a high microbial variation in the gut seems to be remarkably important for the efficacy of immunotherapy, interfering with innate immunity. Metabolic and immunity pathways are related with specific gut microbiota composition. Various studies have explored the composition of gut microbiota in correlation with the effectiveness of immunotherapy. Colorectal cancer (CRC) patients have gained little benefit from immunotherapy until now. Only mismatch repair-deficient/microsatellite-unstable tumors seem to respond positively to immunotherapy. However, gut microbiota could be the key to expanding the use of immunotherapy to a greater range of CRC patients.

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Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

OncoImmunology ◽

10.1080/2162402x.2020.1794423 ◽

2020 ◽

Vol 9 (1) ◽

pp. 1794423

Author(s):

Romain Daillère ◽

Bertrand Routy ◽

Anne-Gaëlle Goubet ◽

Alexandria Cogdill ◽

Gladys Ferrere ◽

...

Keyword(s):

Gut Microbiota ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Microbiota Composition ◽

Gut Microbiota Composition

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Association of dietary fibre intake and gut microbiota in adults

British Journal Of Nutrition ◽

10.1017/s0007114518002465 ◽

2018 ◽

Vol 120 (9) ◽

pp. 1014-1022 ◽

Cited By ~ 20

Author(s):

Daniel Lin ◽

Brandilyn A. Peters ◽

Charles Friedlander ◽

Hal J. Freiman ◽

James J. Goedert ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Risk ◽

Gut Microbiota ◽

Dietary Fibre ◽

Meta Analysis ◽

Microbiota Composition ◽

Fibre Intake ◽

Dietary Fibre Intake ◽

The Relationship ◽

Gut Microbiota Composition

AbstractIncreasing evidence indicates that gut microbiota may influence colorectal cancer risk. Diet, particularly fibre intake, may modify gut microbiota composition, which may affect cancer risk. We investigated the relationship between dietary fibre intake and gut microbiota in adults. Using 16S rRNA gene sequencing, we assessed gut microbiota in faecal samples from 151 adults in two independent study populations: National Cancer Institute (NCI), n 75, and New York University (NYU), n 76. We calculated energy-adjusted fibre intake based on FFQ. For each study population with adjustment for age, sex, race, BMI and smoking, we evaluated the relationship between fibre intake and gut microbiota community composition and taxon abundance. Total fibre intake was significantly associated with overall microbial community composition in NYU (P=0·008) but not in NCI (P=0·81). In a meta-analysis of both study populations, higher fibre intake tended to be associated with genera of class Clostridia, including higher abundance of SMB53 (fold change (FC)=1·04, P=0·04), Lachnospira (FC=1·03, P=0·05) and Faecalibacterium (FC=1·03, P=0·06), and lower abundance of Actinomyces (FC=0·95, P=0·002), Odoribacter (FC=0·95, P=0·03) and Oscillospira (FC=0·96, P=0·06). A species-level meta-analysis showed that higher fibre intake was marginally associated with greater abundance of Faecalibacterium prausnitzii (FC=1·03, P=0·07) and lower abundance of Eubacterium dolichum (FC=0·96, P=0·04) and Bacteroides uniformis (FC=0·97, P=0·05). Thus, dietary fibre intake may impact gut microbiota composition, particularly class Clostridia, and may favour putatively beneficial bacteria such as F. prausnitzii. These findings warrant further understanding of diet–microbiota relationships for future development of colorectal cancer prevention strategies.

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The Emerging Role of the Gut Microbiome in the Cancer Response to Immune Checkpoint Inhibitors: A Narrative Review

Journal of Immunotherapy and Precision Oncology ◽

10.36401/jipo-21-10 ◽

2021 ◽

Author(s):

Ghada Araji ◽

Julian Maamari ◽

Fatima Ali Ahmad ◽

Rana Zareef ◽

Patrick Chaftari ◽

...

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Therapeutic Interventions ◽

The Impact ◽

The Relationship ◽

Gut Microbiota Composition

ABSTRACT The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the care of cancer patients. However, the response to ICI therapy exhibits substantial interindividual variability. Efforts have been directed to identify biomarkers that predict the clinical response to ICIs. In recent years, the gut microbiome has emerged as a critical player that influences the efficacy of immunotherapy. An increasing number of studies have suggested that the baseline composition of a patient's gut microbiota and its dysbiosis are correlated with the outcome of cancer immunotherapy. This review tackles the rapidly growing body of evidence evaluating the relationship between the gut microbiome and the response to ICI therapy. Additionally, this review highlights the impact of antibiotic-induced dysbiosis on ICI efficacy and discusses the possible therapeutic interventions to optimize the gut microbiota composition to augment immunotherapy efficacy.

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Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors

Biomolecules ◽

10.3390/biom10071061 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1061 ◽

Cited By ~ 1

Author(s):

Alexandre Perrier ◽

Audrey Didelot ◽

Pierre Laurent-Puig ◽

Hélène Blons ◽

Simon Garinet

Keyword(s):

Dna Methylation ◽

Tumor Microenvironment ◽

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Response Rates ◽

Cell Phenotype ◽

Epigenetic Biomarkers

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.

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Host–MicroRNA–Microbiota Interactions in Colorectal Cancer

Genes ◽

10.3390/genes10040270 ◽

2019 ◽

Vol 10 (4) ◽

pp. 270 ◽

Cited By ~ 4

Author(s):

Ce Yuan ◽

Clifford J. Steer ◽

Subbaya Subramanian

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Tumor Cells ◽

Immune Cell ◽

Review Article ◽

Microbiota Composition ◽

Cell Fractions ◽

High Level ◽

Gut Microbiota Composition

Changes in gut microbiota composition have consistently been observed in patients with colorectal cancer (CRC). Yet, it is not entirely clear how the gut microbiota interacts with tumor cells. We know that tumor cells undergo a drastic change in energy metabolism, mediated by microRNAs (miRNAs), and that tumor-derived miRNAs affect the stromal and immune cell fractions of the tumor microenvironment. Recent studies suggest that host intestinal miRNAs can also affect the growth and composition of the gut microbiota. Our previous CRC studies showed a high-level of interconnectedness between host miRNAs and their microbiota. Considering all the evidence to date, we postulate that the altered nutrient composition and miRNA expression in the CRC microenvironment selectively exerts pressure on the surrounding microbiota, leading to alterations in its composition. In this review article, we present our current understanding of the role of miRNAs in mediating host–microbiota interactions in CRC.

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Effects of Prebiotic Supplement on Gut Microbiota, Drug Bioavailability and Adverse Effects in Patients with Colorectal Cancer at Different Primary Tumor Locations Receiving Chemotherapy: Study Protocol for a Randomized Clinical Trial

10.21203/rs.3.rs-907838/v1 ◽

2022 ◽

Author(s):

Yanmin Li ◽

Hong Cao ◽

Bojian Fei ◽

Chuanqing Bao ◽

Jianmin Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trial ◽

Adverse Effects ◽

Gut Microbiota ◽

Primary Tumor ◽

Response To Therapy ◽

Control Group ◽

Microbiota Composition ◽

Drug Bioavailability ◽

Gut Microbiota Composition

Abstract Background: The prevalence of colorectal cancer (CRC) worldwide is a huge challenge to human health. Primary tumor locations found to impact prognosisand response to therapy. The important role of gut microbiota in the progression and treatment of CRC has led to many attempts of alleviating chemotherapy-induced adverse effects using microecologics. However, the underlying mechanism of the difference in the prognosis of different primary tumor locations and the synergistic effect of prebiotics on chemotherapy need to be further elucidated. This study aims to explore the differences in tumor microbiota and examine the effectiveness of xylooligosaccharides (XOS) on gut microbiota, adverse effects, and bioavailability of chemotherapy drugs in CRC patients at different primary tumor locations.Methods: This is a double-blinded, randomized, parallel controlled clinical trial. Participants with left-sided CRC (LSCRC, n = 50) and right-sided CC (RSCC, n = 50) will randomly allocated to prebiotic group (n = 25) or control group (n = 25) and will receive either a daily XOS (3 g/d) or placebo, respectively, for 12 weeks. The primary outcomes will be the differences in the mucosa microbiota composition at different tumor locations, and differences in gut microbiota composition, adverse effects, and blood concentration of capecitabine posttreatment. The secondary outcomes will include other blood indicators, short-chain fatty acids (SCFAs) concentration, quality of life, and mental health.Discussion: This study will reveal the potential benefits of prebiotic for improving the gut microbiota composition, alleviating the adverse effects, and improving the efficacy of chemotherapy in patients with CRC. In addition, this study will provide data on the different distribution of tumor microbiota and the different changes of gut microbiota during treatment in LSCRC and RSCC, which may provide novel insights into personalized cancer treatment strategies based on primary tumor locations and gut microbiota in the future.Trial registration: Chinese Clinical Trial Registry(www.chictr.org.cn): ChiCTR2100046237. Registered on 12 May 2021.

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Antibiotic-Related Changes in Microbiome: The Hidden Villain behind Colorectal Carcinoma Immunotherapy Failure

International Journal of Molecular Sciences ◽

10.3390/ijms22041754 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1754

Author(s):

Tsvetelina Velikova ◽

Boris Krastev ◽

Stefan Lozenov ◽

Radostina Gencheva ◽

Monika Peshevska-Sekulovska ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Carcinoma ◽

Immune Responses ◽

Intestinal Microbiota ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Intestinal Bacteria ◽

Molecular Pathways ◽

Microbiota Composition ◽

Direct Observations

The interplay between drugs and microbiota is critical for successful treatment. An accumulating amount of evidence has identified the significant impact of intestinal microbiota composition on cancer treatment response, particularly immunotherapy. The possible molecular pathways of the interaction between immune checkpoint inhibitors (ICIs) and the microbiome can be used to reverse immunotherapy tolerance in cancer by using various kinds of interventions on the intestinal bacteria. This paper aimed to review the data available on how the antibiotic-related changes in human microbiota during colorectal cancer (CRC) treatment can affect and determine ICI treatment outcomes. We also covered the data that support the potential intimate mechanisms of both local and systemic immune responses induced by changes in the intestinal microbiota. However, further better-powered studies are needed to thoroughly assess the clinical significance of antibiotic-induced alteration of the gut microbiota and its impact on CRC treatment by direct observations of patients receiving antibiotic treatment.

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Long-term hexavalent chromium exposure facilitates colorectal cancer in mice associated with changes in gut microbiota composition

Food and Chemical Toxicology ◽

10.1016/j.fct.2020.111237 ◽

2020 ◽

Vol 138 ◽

pp. 111237 ◽

Cited By ~ 4

Author(s):

Zecai Zhang ◽

Hongyang Cao ◽

Ning Song ◽

Lixiao Zhang ◽

Yongguo Cao ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Hexavalent Chromium ◽

Microbiota Composition ◽

Chromium Exposure ◽

Gut Microbiota Composition

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Immunotherapy in gliomas: Are we reckoning without the innate immunity?

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738419843378 ◽

2019 ◽

Vol 33 ◽

pp. 205873841984337 ◽

Cited By ~ 3

Author(s):

Marco Flavio Michele Vismara ◽

Annalidia Donato ◽

Natalia Malara ◽

Ivan Presta ◽

Giuseppe Donato

Keyword(s):

Innate Immunity ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Barrier Properties ◽

Chemotherapeutic Agents ◽

Innate And Adaptive Immunity ◽

Tumor Associated Macrophage ◽

Molecular Features ◽

The Central Nervous System ◽

Tumors Classification

Innate immunity plays a central role in neoplasms, including those affecting the central nervous system (CNS). Nowadays, tumors classification, especially that regarding gliomas, is based on molecular features such as mutations in isocitrate dehydrogenase (IDH) genes and the presence of co-deletion 1p/19q. Therapy, in most cases, is based on surgery, radiotherapy, and pharmacological treatment with chemotherapeutic agents such as temozolomide. However, the results of the treatments, after many decades, are not completely satisfactory. There is a class of drugs, used to treat cancer, which modulates immune response; in this class, the immune checkpoint inhibitors and vaccines play a prominent role. These drugs were evaluated for the treatment of gliomas, but they exhibited a poor outcome in clinical trials. Those scarce results could be due to the response of tumor-associated macrophage that creates imbalances between innate and adaptive immunity and changes in blood–brain barrier properties. Here, we have briefly reviewed the current literature on this topic, focusing on the possible role for innate immunity in the failure of immunotherapies against brain tumors.

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