The Role of the Microbiome in Pancreatic Cancer

Miyabayashi, Koji; Ijichi, Hideaki; Fujishiro, Mitsuhiro

doi:10.3390/cancers14184479

Cited by 16 publications

(13 citation statements)

References 137 publications

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“…Our results support the notion that access of lymphocytes to PDAC tumors is limited by the cellular components of the TME and potentially the nature of mutations driving the malignancy 49 . By characterizing the differing stromal features of distinct orthotopic tumors, we can better adapt our pre-clinical testing of cellular or other immunotherapy approaches to maximize clinical relevance and applicability.…”

Section: Discussionsupporting

confidence: 86%

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell therapy

Horvat,

Karpovsky,

Phillips

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease; ∼12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted outcomes in PDAC patients, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMM) for PDAC are considered a “gold-standard” as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and cost of colony maintenance. We characterized the immunologic features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC models using two mouse cell lines, KPC-Luc and MT-5, isolated from KPC-GEMM mouse models (KrasLSL-G12D/+p53-/-and KrasLSL-G12D/+p53LSL-R172H/+, respectively). The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate KPC-Luc tumors, which have less stroma. Albeit CD4+ T cells were similarly detected in MT-5 tumors compared to KPC-GEMM in mice. Interestingly, we found that CAR T cells redirected to recognize mesothelin on these tumors that signal via CD3σ and 41BB (Meso-41BBσ-CAR T cells) post antigen recognition infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors. Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve in-depth study of how to overcome barriers that limit anti-tumor activity of adoptively transferred T cells.

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Section: Discussionsupporting

confidence: 86%

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell therapy

Horvat,

Karpovsky,

Phillips

et al. 2023

Preprint

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“…In recent years, multiple studies have reported an association between gut dysbiosis and pancreatic cancer, with increased levels of Bacteroides , and decreased levels of Firmicutes , while at higher taxonomic levels, Veillonellaceae was predominant and Clostridiaceae was decreased. It was observed that smoking cessation results in an increase in Firmicutes and a decrease in Bacteroides and Proteobacteria , thus highlighting the importance of tobacco abstinence in a lifestyle intervention for cancer patients [ 78 ].…”

Section: Gut Microbiota Profile In Pancreatitismentioning

confidence: 99%

Exploring the Microbial Landscape: Gut Dysbiosis and Therapeutic Strategies in Pancreatitis—A Narrative Review

Lupu,

Bratu,

Trandafir

et al. 2024

Biomedicines

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The gut microbiota is emerging as an important contributor to the homeostasis of the human body through its involvement in nutrition and metabolism, protection against pathogens, and the development and modulation of the immune system. It has therefore become an important research topic in recent decades. Although the association between intestinal dysbiosis and numerous digestive pathologies has been thoroughly researched, its involvement in pancreatic diseases constitutes a novelty in the specialized literature. In recent years, growing evidence has pointed to the critical involvement of the pancreas in regulating the intestinal microbiota, as well as the impact of the intestinal microbiota on pancreatic physiology, which implies the existence of a bidirectional connection known as the “gut–pancreas axis”. It is theorized that any change at either of these levels triggers a response in the other component, hence leading to the evolution of pancreatitis. However, there are not enough data to determine whether gut dysbiosis is an underlying cause or a result of pancreatitis; therefore, more research is needed in this area. The purpose of this narrative review is to highlight the role of gut dysbiosis in the pathogenesis of acute and chronic pancreatitis, its evolution, and the prospect of employing the microbiota as a therapeutic intervention for pancreatitis.

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“…The newest pilot study is designed to modulate the microbiome with ciprofloxacin and metronidazole to further enable the efficacy of neoadjuvant checkpoint-based immunotherapy with pembrolizumab following mFOLFIRINOX chemotherapy in surgically resectable PDAC (NCT05462496). Preclinical studies proved that the alteration of the microbiome modulates TME and the immune system, which affects the efficacy of chemotherapy and immune-targeted therapies in PC [ 133 ]. Drugs for PC with different mechanisms of action are summarised in Table 2 .…”

Section: Othersmentioning

confidence: 99%

New Treatment Options in Metastatic Pancreatic Cancer

Fudalej

Kwaśniewska

Nurzyński

et al. 2023

Cancers

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Pancreatic cancer (PC) is the seventh leading cause of cancer death across the world. Poor prognosis of PC is associated with several factors, such as diagnosis at an advanced stage, early distant metastases, and remarkable resistance to most conventional treatment options. The pathogenesis of PC seems to be significantly more complicated than originally assumed, and findings in other solid tumours cannot be extrapolated to this malignancy. To develop effective treatment schemes prolonging patient survival, a multidirectional approach encompassing different aspects of the cancer is needed. Particular directions have been established; however, further studies bringing them all together and connecting the strengths of each therapy are needed. This review summarises the current literature and provides an overview of new or emerging therapeutic strategies for the more effective management of metastatic PC.

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The Role of the Microbiome in Pancreatic Cancer

Cited by 16 publications

References 137 publications

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell therapy

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell therapy

Exploring the Microbial Landscape: Gut Dysbiosis and Therapeutic Strategies in Pancreatitis—A Narrative Review

New Treatment Options in Metastatic Pancreatic Cancer

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