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

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

Cancers ◽

10.3390/cancers13010043 ◽

2020 ◽

Vol 13 (1) ◽

pp. 43

Author(s):

Asimina Koulouridi ◽

Ippokratis Messaritakis ◽

Nikolaos Gouvas ◽

John Tsiaoussis ◽

John Souglakos

Keyword(s):

Colorectal Cancer ◽

Innate Immunity ◽

Gut Microbiota ◽

Solid Tumors ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Microbiota Composition ◽

Innate And Adaptive Immunity ◽

Gut Microbiota Composition

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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Gut Microbiota and Immune Checkpoint Inhibitors-Based Immunotherapy

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210706110713 ◽

2021 ◽

Vol 21 ◽

Author(s):

Mingming Tian ◽

Si Zhang ◽

Yujen Tseng ◽

Xizhong Shen ◽

Ling Dong ◽

...

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Recent Progress ◽

Checkpoint Inhibitors ◽

Antitumor Response ◽

Number Of Patients ◽

Cancer Types ◽

Patients Experience

: Application of immune checkpoint inhibitors (ICIs) is a major breakthrough in the field of cancer therapy, which has displayed tremendous potential in various types of malignancies. However, their response rates range widely in different cancer types and a significant number of patients experience immune-related adverse effects (irAEs) induced by these drugs, limiting the proportion of patients who can truly benefit from ICIs. Gut microbiota has gained increasing attention due to its emerging role in regulating the immune system. In recent years, numerous studies have shown that gut microbiota can modulate antitumor response, as well as decrease the risk of colitis due to ICIs in patients receiving immunotherapy. The present review analyzed recent progress of relevant basic and clinical studies in this area and explored new perspectives to enhance the efficacy of ICIs and alleviate associated irAEs via manipulation of the gut microbiota.

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Tu1796 ALTERNATION OF GUT MICROBIOTA IN PATIENT WITH IMMUNE CHECKPOINT INHIBITORS

Gastroenterology ◽

10.1016/s0016-5085(20)33584-8 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-1164-S-1165

Author(s):

Yuki Hirata ◽

Hideki Tawa ◽

Yasuyoshi Tanaka ◽

Kazuki Kakimoto ◽

Ken Kawakami ◽

...

Keyword(s):

Gut Microbiota ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors

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Are Long-Chain Polyunsaturated Fatty Acids the Link between the Immune System and the Microbiome towards Modulating Cancer?

Medicines ◽

10.3390/medicines5030102 ◽

2018 ◽

Vol 5 (3) ◽

pp. 102 ◽

Cited By ~ 9

Author(s):

Leodevico Ilag

Keyword(s):

Fatty Acids ◽

Immune System ◽

Gut Microbiota ◽

Polyunsaturated Fatty Acids ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Optimal Level ◽

Common Denominator ◽

Long Chain

Three recent studies revealed synergy between immune-checkpoint inhibitors and the microbiome as a new approach in the treatment of cancer. Incidentally, there has been significant progress in understanding the role of polyunsaturated fatty acids (PUFAs) in modulating cancer and the immune system, as well as in regulating the microbiome. Inflammation seems to be the common denominator among these seemingly unrelated biological entities—immune system, the microbiome, and long-chain polyunsaturated fatty acids (LC-PUFAs). This commentary presents a hypothesis proposing the existence of an optimal level of LC-PUFAs that nurtures the suitable gut microbiota preventing dysbiosis. This synergy between optimal LC-PUFAs and gut microbiota helps the immune system overcome the immunosuppressive tumour microenvironment including enhancing the efficacy of immune checkpoint inhibitors. A model on how LC-PUFAs (such as omega(n)-3 and n-6 fatty acids) forms a synergistic triad with the immune system and the microbiome in regulating inflammation to maintain homeostasis is presented. The principles underlying the hypothesis provide a basis in managing and even preventing cancer and other chronic diseases associated with inflammation.

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Manipulating Gut Microbiota Composition to Enhance the Therapeutic Effect of Cancer Immunotherapy

Integrative Cancer Therapies ◽

10.1177/1534735419876351 ◽

2019 ◽

Vol 18 ◽

pp. 153473541987635 ◽

Cited By ~ 4

Author(s):

Ming Yi ◽

Dechao Jiao ◽

Shuang Qin ◽

Qian Chu ◽

Anping Li ◽

...

Keyword(s):

Gut Microbiota ◽

Cancer Immunotherapy ◽

Treatment Effect ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Adoptive Cell Transfer ◽

Microbiota Composition ◽

Cancer Types ◽

Xenograft Models ◽

Gut Microbiota Composition

In the past decade, a growing set of immunotherapies including immune checkpoint blockade, chimeric antigen receptor T cells, and bispecific antibodies propelled the advancement of oncology therapeutics. Accumulating evidence demonstrates that immunotherapy could eliminate tumors better than traditional chemotherapy or radiotherapy with lower risk of adverse events in numerous cancer types. Unfortunately, a substantial proportion of patients eventually acquire resistance to immunotherapy. By analyzing the differences between immunotherapy-sensitive and immunotherapy-resistant populations, it was noticed that the composition of gut microbiota is closely related to treatment effect. Moreover, in xenograft models, interventional regulation of gut microbiota could effectively enhance efficacy and relieve resistance during immunotherapy. Thus, we believe that gut microbiota composition might be helpful to explain the heterogeneity of treatment effect, and manipulating gut microbiota could be a promising adjuvant treatment for cancer immunotherapy. In this mini review, we focus on the latest understanding of the cross-talk between gut microbiota and host immunity. Moreover, we highlight the role of gut microbiota in cancer immunotherapy including immune checkpoint inhibitor and adoptive cell transfer.

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Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome

International Journal of Molecular Sciences ◽

10.3390/ijms22157800 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7800

Author(s):

Sally Temraz ◽

Farah Nassar ◽

Firas Kreidieh ◽

Deborah Mukherji ◽

Ali Shamseddine ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Gut Microbiota ◽

Gut Microbiome ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Hepatic Carcinogenesis ◽

Host Metabolism

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.

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