Therapeutic potential of microbial modulation in pancreatic cancer
Vidhi Chandra and Florencia McAllister
Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is an aggressive disease with a poor prognosis.1 Surgery is the only potential curative treatment, but it is only possible in patients with early-stage disease, and most patients present with non-resectable disease.1 Even in patients who undergo resection, the recurrence rate is very high due to early systemic dissemination.2 Combinatorial chemotherapy remains the standard of care for patients with advanced disease, but responses to it are heterogeneous, and its toxicity limits treatment duration.3–5 Results from clinical trials of single-agent immunotherapy have not proven its efficacy in patients with pancreatic cancer, not even when used with chemotherapy or other immunotherapeutic agents.6–8 A highly immunosuppressive tumour microenvironment (TME) has been postulated as one of the main reasons for the lack of efficacy of immunotherapy for pancreatic cancer.9–11 Therefore, novel strategies that modulate the suppressive TME are urgently needed.
The GI tract is the largest reservoir of microbes, which play important roles in modulating metabolism and immunity through interaction with host cells.12 The discovery of the association between infection with the bacterium Helicobacter pylori and the incidence of gastritis and peptic ulcer disease earned Barry Marshall and Robin Warren the Nobel Prize in Physiology or Medicine in 2005, underscoring the pivotal role of the microbiota in influencing inflammatory conditions which may predispose to cancer.13 The microbial α-diversity is a metric that quantifies the number of different species within a defined sample.14 15 In patients with many malignancies, including colorectal, breast and pancreatic cancer, the α-diversity of the gut microbiota is lower than that in healthy controls.16–18 With respect to clinical outcomes, the gut microbial α-diversity is higher in patients with melanoma that responded to immunotherapy than in those unresponsive.19 In this review, we highlight recent studies analysing microbes present in various compartments (oral cavity, gut, cysts and pancreatic tumours) in patients with pancreatic cancer, as well as murine studies. We also discuss various strategies for microbial modulation. A summary of the published data on enriched microbes at different sites in clinical studies and murine models of pancreatic cancer is included in table 1.
Overview of clinical FMT trials by status (A), clinical phase (B), delivery mode (C) and cancer (D) reported in ClinicalTrials.gov as of September 2020. autoimm, autoimmune; FMT, faecal microbial transplant; inflamm, inflammatory.