Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis

Yu, Amy I.; Zhao, Lili; Eaton, Kathryn A.; Ho, Sharon L.; Chen, Jiachen; Poe, Sara; Becker, James M.; Gonzalez, Allison; McKinstry, Delaney; Hasso, Muneer; Mendoza-Castrejon, Jonny; Whitfield, Joel; Koumpouras, Charles C.; Schloss, Patrick D.; Martens, Eric C.; Chen, Grace Y.

doi:10.1016/j.celrep.2020.03.035

Cited by 128 publications

(79 citation statements)

References 92 publications

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“…Indeed, gnotobiotic mice colonized with a Helicobacter -dominated microbiota from wild mice are partially protected from CRC induced by AOM-DSS (Rosshart et al, 2017). Conversely, some laboratory microbiomes containing other Helicobacter strains decrease the effectiveness of CD8 + T cell control over colorectal tumors (Yu et al, 2020), so it will be important to tease out the specific mechanisms employed by different strains of Helicobacter to induce mucosal immune responses. In humans, colonization with Helicobacter pylori has plummeted 2-3 fold over the past few decades with the lowest rates of infection being seen in young people (Jiang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Microbiome-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer

Overacre

Cillo

Bumgarner

et al. 2021

Preprint

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SummaryColorectal cancer (CRC) is a common and deadly disease, and patients with metastatic tumors often fail to respond to therapy. While select members of the microbiome are associated with improved anti-tumor immunity, mechanistic understanding of how the microbiome provides a benefit is lacking. We show that modification of the CRC-associated microbiome with a single immunogenic commensal bacteria can alter T cell differentiation, inhibit tumor growth, and increase survival. Microbiome-driven control of CRC required the formation of colonic tertiary lymphoid structures (TLS) and increased infiltration of the tumor with cytotoxic immune cells. In the context of CRC, CD4+ T cells specific to the newly introduced commensals differentiated into T follicular helper cells and were necessary for the formation of TLS, immune infiltration of the tumor, and control over CRC. Thus, modification of the intestinal T cell response by the microbiome can be used to augment anti-tumor immunity in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Microbiome-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer

Overacre

Cillo

Bumgarner

et al. 2021

Preprint

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“…Although the exact mechanisms remain to be discovered, a growing number of preclinical animal model studies and clinical trials of immunotherapies suggest that the host microbiome is a critical determinant for the variable host responses to different therapy modalities [18]. Yu et al demonstrated that the same type of pro-inflammatory cells induced due to dysbiosis leads to increased T cell exhaustion in the tumor microenvironment [19]. Gut microbiota dysbiosis also increases the intestinal barrier's permeability, favoring bacterial translocation, macrophages activation, and the consequent establishment of chronic pro-tumorigenic inflammation.…”

Section: Microbiome Local and Systemic Immune Responses And Cancermentioning

confidence: 99%

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

Velikova

Krastev²,

Lozenov

et al. 2021

IJMS

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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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“…58 When considering how these mechanisms may link to the gut microbiota, it is known that gut microbiota are key regulators of CD8+ T cell function. 59 The gut microbiota that produce SCFA can promote the memory potential of antigen-activated CD8+T cells. 60 In terms of mounting a response directly against the SARS-CoV-2 virus, it has been demonstrated that the SCFAs, butyrate and, to a lesser extent, propionate directly modulate gene expression of CD8+ cytotoxic T lymphocytes (CTLs) and Tc17 cells.…”

Section: Microbiome-immune Interactionsmentioning

confidence: 99%

The gut microbiome: an under-recognised contributor to the COVID-19 pandemic?

Segal

Mak

Mullish

et al. 2020

Therap Adv Gastroenterol

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The novel coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus has spread rapidly across the globe, culminating in major global morbidity and mortality. As such, there has been a rapid escalation in scientific and clinical activity aimed at increasing our comprehension of this virus. This volume of work has led to early insights into risk factors associated with severity of disease, and mechanisms that underpin the virulence and dynamics involved in viral transmission. These insights ultimately may help guide potential therapeutics to reduce the human, economic and social impact of this pandemic. Importantly, the gastrointestinal (GI) tract has emerged as an important organ influencing propensity to, and potentially severity of, COVID-19 infection. Furthermore, the gut microbiome has been linked to a variety of risk factors for COVID-19 infection, and manipulation of the gut microbiome is an attractive potential therapeutic target for a number of diseases. While data profiling the gut microbiome in COVID-19 infection to date are limited, they support the possibility of several routes of interaction between COVID-19, the gut microbiome, angiotensin converting enzyme 2 (ACE-2) expression in the small bowel and colon and gut inflammation. This article will explore the evidence that implicates the gut microbiome as a contributing factor to the pathogenesis, severity and disease course of COVID-19, and speculate about the gut microbiome’s capability as a therapeutic avenue against COVID-19. Lay summary It has been noted that certain baseline gut profiles of COVID-19 patients are associated with a more severe disease course, and the gut microbiome impacts the disease course of several contributory risk factors to the severity of COVID-19. A protein called ACE-2, which is found in the small intestine among other sites, is a key receptor for COVID-19 virus entry; there is evidence that the gut microbiome influences ACE-2 receptor expression, and hence may play a role in influencing COVID-19 infectivity and disease severity. Furthermore, the gut microbiome plays a significant role in immune regulation, and hence may be pivotal in influencing the immune response to COVID-19. In terms of understanding COVID-19 treatments, the gut microbiome is known to interact with several drug classes being used to target COVID-19 and should be factored into our understanding of how patients respond to treatment. Importantly, our understanding of the role of the gut microbiome in COVID-19 infection remains in its infancy, but future research may potentially aid our mechanistic understanding of viral infection, and new ways in which we might approach treating it.

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Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis

Abstract: Highlights d Dysbiosis can lead to increased colon tumor susceptibility and CD8 + IFNg + T cells d Increased colon CD8 + IFNg + T cells are associated with more inflammation and tumors d Dysbiosis and increased tumorigenesis are associated with greater T cell exhaustion

Cited by 128 publications

References 92 publications

Microbiome-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer

Microbiome-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer

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

The gut microbiome: an under-recognised contributor to the COVID-19 pandemic?

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